Stapled peptides and methods thereof

Abstract

Among other things, the present disclosure provides various useful agents. In some embodiments, provided agents can bind to beta-catenin. In some embodiments, the present disclosure provides technologies for modulating beta-catenin levels in a system. In some embodiments, the present disclosure provides technologies for modulating beta-catenin functions. In some embodiments, the present disclosure provides technologies for preventing and / or treating conditions, disorders or diseases associated with beta-catenin.

Description

Attorney Docket Number: 2012675-0389 STAPLED PEPTIDES AND METHODS THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No.63 / 662,391, filed June 20, 2024, the entirety of which is incorporated herein as reference. BACKGROUND

[0002] Stapled peptides are useful for various applications. For example, as biologically active agents, they can be utilized to modulate various biological functions. SUMMARY

[0003] Among other things, the present disclosure provides powerful technologies (e.g., agents (e.g., those that are or comprise peptides, in many embodiments, stapled peptides), compositions, methods, etc.) for modulating various biological functions. In some embodiments, the present disclosure provides technologies that can reduce beta-catenin levels. In some embodiments, provided technologies can bind polypeptide degradation machinery components, e.g., E3 ubiquitin ligases. In some embodiments, compared to reference technologies that do not include structures that can bind polypeptide degradation machinery components, e.g., E3 ubiquitin ligases, provided technologies can provide various different properties and activities, e.g., PK, PD, etc., which can be useful for various applications including therapeutic applications. In some embodiments, provided technologies are useful for treating various conditions, diseases or disorders.

[0004] In some embodiments, the present disclosure provides agents that comprise a target binding moiety, a linker, and a moiety that can bind a polypeptide degradation machinery component (e.g., an E3 ubiquitin ligase). In some embodiments, the present disclosure provides agents that comprise a target binding moiety, a linker, and an E3 ubiquitin ligase binding moiety. In some embodiments, a target binding moiety is or comprises a stapled peptide moiety. In some embodiments, a target binding moiety can bind to beta- catenin.

[0005] In some embodiments, the present disclosure provides an agent, wherein the agent has the structure of: TBM-L0-LBM, or a salt thereof, wherein each variable is independently as described herein. In some embodiments, target binding moiety is or comprises a stapled peptide moiety and can bind to beta-catenin, and LBM can bind an E3 ubiquitin ligase.

[0006] In some embodiments, there is a single staple in a stapled peptide. In some embodiments, stapled peptides comprise multiple staples. In some embodiments, the present disclosure provides agents, e.g., agents that are or comprise stapled peptides that comprise three or more staples. In some embodiments, the present disclosure provides agents, e.g., agents that are or comprise stapled peptides that comprise three or more Page 1 of 884 12834799v1Attorney Docket Number: 2012675-0389 staples within 10-20 amino acid residues, e.g., 10-15, 11-15, 11-14, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive amino acid residues. In some embodiments, the present disclosure provides agents, e.g., agents that are or comprise stapled peptides that comprise three or more staples within 11 consecutive amino acid residues. In some embodiments, the present disclosure provides agents, e.g., agents that are or comprise stapled peptides that comprise three or more staples within 14 consecutive amino acid residues. In some embodiments, within such numbers of amino acid residues there are three staples. In some embodiments, within such numbers of consecutive amino acid residues there are four staples. Without the intention to be limited by theory, in some embodiments, provided agents, e.g., agents that are or comprise stapled peptides have increased rigidity than reference peptides (e.g., unstapled peptides, or stapled peptides having fewer staples (in some embodiments, fewer staples within certain numbers of amino acid residues as described herein), etc.). In some embodiments, provided agents, e.g., agents that are or comprise stapled peptides demonstrate various desired properties and / or activities. In some embodiments, provided agents, e.g., agents that are or comprise stapled peptides provide improved desired properties and / or activities than reference peptides (e.g., unstapled peptides, or stapled peptides having fewer staples (in some embodiments, fewer staples within certain numbers of amino acid residues as described herein), etc.).

[0007] In some embodiments, the present disclosure provides certain linker and / or E3 ubiquitin ligase binding moiety technologies that can provide improved affinity and / or activity compared to reference technologies comprising the same target binding moieties but different linker and / or E3 ubiquitin ligase biding moiety technologies. In some embodiments, the present disclosure provides linker technologies that can provide improved affinity and / or activity. In some embodiments, the present disclosure provides E3 ubiquitin ligase binding moiety technologies than can provide improved affinity and / or activity. In some embodiments, provided agents comprise such linker and / or E3 ubiquitin ligase binding moiety technologies and can provide improved affinity and / or activity. In some embodiments, they can provide improved affinity to targets (e.g., beta-catenin) and / or E3 ubiquitin ligases. In some embodiments, they can provide improved activity. In some embodiments, they can provide reduced levels of beta-catenin compared to reference technologies (e.g., agents comprising the same target binding moieties but different linker and / or E3 ubiquitin ligase binding moieties).

[0008] In some embodiments, the present disclosure provides technologies for modulating one or more functions of beta-catenin. Particularly, in some embodiments, the present disclosure provides various agents, e.g., agents that are or comprise peptides, in many instances stapled peptides, that can bind to beta-catenin and modulate its functions. As demonstrated herein, in some embodiments, the present disclosure binds agents that can interact with beta-catenin at a unique set of residues. In some embodiments, a binding site comprises one or more or all of the set of residues. In some embodiments, provided agents interact with one or more of a set of residues that are or correspond to the following residues of SEQ ID NO: 1: A305, Y306, G307, N308, Q309, K312, R342, K345, V346, V349, Q375, R376, Q379, N380, L382, W383, R386, N387, D413, N415, V416, T418, and C419. In some embodiments, provided agents interact with one or more of Page 2 of 884 12834799v1Attorney Docket Number: 2012675-0389 amino acid residue that are or correspond to A305, Y306, G307, N308, Q309, K312, R342, K345, V346, V349, Q375, Q379, N380, L382, W383, R386, N387, D413, N415, V416, T418, and C419 of SEQ ID NO: 1. In some embodiments, provided agents interact with one or more of amino acid residues that are or correspond to A305, Y306, G307, N308, Q309, K312, K345, V346, V349, Q379, N380, L382, W383, R386, N387, D413, N415, V416, T418, and C419 of SEQ ID NO: 1. In some embodiments, provided agents interact with one or more of amino acid residues that are or correspond to G307, K312, K345, W383, N387, D413, and N415 of SEQ ID NO: 1. In some embodiments, provided agents interact with one or more of amino acid residues that are or correspond to K312, K345, R386 and W383 of SEQ ID NO: 1. In some embodiments, provided agents interact with one or more of a set of residues that are or correspond to the following residues of SEQ ID NO: 1: G307, K312, K345, Q379, L382, W383, N387, N415, and V416. In some embodiments, provided agents interact with all of a set of residues that are or correspond to the following residues of SEQ ID NO: 1: Y306, G307, K312, K345, Q379, L382, W383, N387, N415, and V416. In some embodiments, provided agents interact with all of a set of residues that are or correspond to the following residues of SEQ ID NO: 1: G307, K312, K345, Q379, L382, W383, N387, N415, and V416. In some embodiments, provided agents interact with all of a set of residues that are or correspond to the following residues of SEQ ID NO: 1: Y306, G307, K312, K345, Q379, L382, W383, N387, N415, and V416. In some embodiments, provided agents interact with one or more of amino acid residues that are or correspond to K312, K345 and W383 of SEQ ID NO: 1. In some embodiments, provided agents interact with the amino acid residues that are or correspond to K312, K345 and W383 of SEQ ID NO: 1.

[0009] In some embodiments, the present disclosure provides technologies for promoting interactions between a target polypeptide and a second polypeptide. In some embodiments, the present disclosure provides technologies for modulating one or more functions of a target polypeptide by promoting interactions between the target protein and a second polypeptide. In some embodiments, a second polypeptide is or comprises an E3 ubiquitin ligase. In some embodiments, a target polypeptide is or comprises a beta-catenin polypeptide. Particularly, in some embodiments, the present disclosure provides various agents, e.g., agents comprising peptide moieties, in many instances stapled peptide moieties, that can bind beta-catenin and E3 ubiquitin ligase binding moieties that can bind an E3 ubiquitin ligase. In some embodiments, an E3 ubiquitin ligase is CRBN, VHL, UBR4, KLHDC2, KEAP1, or RNF126. In some embodiments, the present disclosure provides various agents, e.g., agents comprising peptide moieties, in many instances stapled peptide moieties, that can bind beta-catenin and E3 ubiquitin ligase binding moieties that can bind CRBN, VHL, UBR4, KLHDC2, KEAP1, or RNF126. In some embodiments, the present disclosure provides various agents, e.g., agents comprising peptide moieties, in many instances stapled peptide moieties, that can bind beta-catenin and ligase binding moieties that can bind CRBN. In some embodiments, the present disclosure provides various agents, e.g., agents comprising peptide moieties, in many instances stapled peptide moieties, that can bind beta-catenin and ligase binding moieties that can bind VHL. In some embodiments, the present disclosure provides various agents, e.g., agents comprising peptide moieties, in many instances stapled Page 3 of 884 12834799v1Attorney Docket Number: 2012675-0389 peptide moieties, that can bind beta-catenin and ligase binding moieties that can bind UBR4. In some embodiments, the present disclosure provides various agents, e.g., agents comprising peptide moieties, in many instances stapled peptide moieties, that can bind beta-catenin and ligase binding moieties that can bind KLHDC2. In some embodiments, the present disclosure provides various agents, e.g., agents comprising peptide moieties, in many instances stapled peptide moieties, that can bind beta-catenin and ligase binding moieties that can bind KEAP1. In some embodiments, the present disclosure provides various agents, e.g., agents comprising peptide moieties, in many instances stapled peptide moieties, that can bind beta-catenin and ligase binding moieties that can bind RNF126. In some embodiments, a peptide moiety is or comprises TBM as described herein. In some embodiments, the present disclosure provides various agents, e.g., agents comprising peptide moieties, in many instances stapled peptide moieties, that can bind target polypeptides, e.g., beta-catenin, and moieties that can bind second polypeptides which can recruit E3 ligases. In some embodiments, an agent can bind a target polypeptide and a second polypeptide which can recruit E3 ligase machinery, and the agent can reduce level of the target polypeptide. In some embodiments, a second polypeptide is HSP90.

[0010] As demonstrated herein, provided technologies can modulate one or more biological processes associated with beta-catenin. In some embodiments, provided agents, e.g., agents that are or comprise stapled peptides, compete with a ligand (e.g., with a member of the T cell factor / lymphoid enhancer factor (TCF / LEF) family of transcription factors) for binding to beta-catenin. In some embodiments, provided agents compete with a ligand for binding to beta-catenin at a particular binding site (e.g., with a member of the T cell factor / lymphoid enhancer factor (TCF / LEF) family of transcription factors at the TCF site on beta- catenin). In some embodiments, provided technologies compete with TCF for interactions with beta-catenin. In some embodiments, binding of provided agents to a beta-catenin site decreases, suppresses and / or blocks binding to beta-catenin by another binding partner (e.g., a kinase). In some embodiments, binding of provided agents blocks binding of beta-catenin by a TCF / LEF family member. In some embodiments, the present disclosure provides agents that can bind to a site of beta-catenin selectively over one of more other binding sites by other ligands (e.g., peptides, proteins, etc.; in some embodiments, a ligand is Axin; in some embodiments, a ligand is Bcl9). In some embodiments, provided technologies modulate one or more beta- catenin functions associated with its interactions with TCF. In some embodiments, provided technologies selectively modulate beta-catenin functions, e.g., functions associated with TCF interactions. In some embodiments, provided technologies selectively modulate beta-catenin functions and do not significantly impact functions that are not associated with beta-catenin (e.g., various functions and / or processes in the Wnt pathway that are not associated with beta-catenin). In some embodiments, provided technologies are useful for inhibiting beta-catenin functions.

[0011] In some embodiments, provided agents are useful for inducing degradation of beta-catenin. In some embodiments, provided agents are useful for inducing degradation of beta-catenin via interactions with an E3 ubiquitin ligase. In some embodiments, provided agents are useful for inducing degradation of beta- Page 4 of 884 12834799v1Attorney Docket Number: 2012675-0389 catenin by binding to beta-catenin and an E3 ubiquitin ligase. In some embodiments, provided agents are useful for inducing degradation of beta-catenin by binding to beta-catenin at the TCF site through a peptide moiety, often a stapled peptide moiety, and an E3 ubiquitin ligase through a ligase binding moiety. In some embodiments, provided agents are useful for inducing degradation of beta-catenin via interactions with an E3 ubiquitin ligase. In some embodiments, provided agents are useful for promoting interactions between beta- catenin and an E3 ubiquitin ligase. In some embodiments, provided agents are useful for promoting interactions between beta-catenin and an E3 ubiquitin ligase by binding to beta-catenin at the TCF site through a peptide moiety, often a stapled peptide moiety, and an E3 ubiquitin ligase through a ligase binding moiety.

[0012] In some embodiments, the present disclosure provides technologies for increasing ubiquitination level of a target polypeptide, e.g., a beta-catenin polypeptide, comprising contacting the target polypeptide with an agent described herein. In some embodiments, the present disclosure provides technologies for reducing level of a target polypeptide, e.g., a beta-catenin polypeptide, comprising contacting the target polypeptide with an agent described herein.

[0013] In some embodiments, provided technologies are useful for preventing or treating various conditions, disorders or diseases including cancer. In some embodiments, the present disclosure provides methods for treating or preventing a condition, disorder or disease associated with beta-catenin, comprising administering to a subject suffered therefrom or susceptible thereto an effective amount of a provided agent or a pharmaceutically acceptable salt thereof. In some embodiments, a condition, disorder or disease is associated with beta-catenin’s interactions with TCF or another polypeptide. In some embodiments, a condition, disorder or disease is hepatocellular cancer. In some embodiments, an agent is administered as a pharmaceutical composition. In some embodiments, the present disclosure provides pharmaceutical compositions which comprise or deliver a provided agent or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, agents can bind to a polypeptide comprising or consisting of SEQ ID NO: 1 (Uniprot ID P35222), or residues 250-450 of SEQ ID NO: 1, or residues 305-419 of SEQ ID NO: 1: Uniprot No. P35222 MATQADLMELDMAMEPDRKAAVSHWQQQSYLDSGIHSGATTTAPSLSGKGNPEEEDVDTSQVLYE WEQGFSQSFTQEQVADIDGQYAMTRAQRVRAAMFPETLDEGMQIPSTQFDAAHPTNVQRLAEPSQ MLKHAVVNLINYQDDAELATRAIPELTKLLNDEDQVVVNKAAVMVHQLSKKEASRHAIMRSPQMV SAIVRTMQNTNDVETARCTAGTLHNLSHHREGLLAIFKSGGIPALVKMLGSPVDSVLFYAITTLHNL LLHQEGAKMAVRLAGGLQKMVALLNKTNVKFLAITTDCLQILAYGNQESKLIILASGGPQALVNIM RTYTYEKLLWTTSRVLKVLSVCSSNKPAIVEAGGMQALGLHLTDPSQRLVQNCLWTLRNLSDAATK QEGMEGLLGTLVQLLGSDDINVVTCAAGILSNLTCNNYKNKMMVCQVGGIEALVRTVLRAGDRED ITEPAICALRHLTSRHQEAEMAQNAVRLHYGLPVVVKLLHPPSHWPLIKATVGLIRNLALCPANHAP LREQGAIPRLVQLLVRAHQDTQRRTSMGGTQQQFVEGVRMEEIVEGCTGALHILARDVHNRIVIRGL NTIPLFVQLLYSPIENIQRVAAGVLCELAQDKEAAEAIEAEGATAPLTELLHSRNEGVATYAAAVLFR Page 5 of 884 12834799v1Attorney Docket Number: 2012675-0389 MSEDKPQDYKKRLSVELTSSLFRTEPMAWNETADLGLDIGAQGEPLGYRQDDPSYRSFHSGGYGQD ALGMDPMMEHEMGGHHPGADYPVDGLPDLGHAQDLMDGLPPGDSNQLAWFDTDL (SEQ ID NO: 1).

[0015] In some embodiments, provided agents specifically interact with one or more residues which are or correspond to residues 305-419 of SEQ ID NO: 1. In some embodiments, provided agents bind to a motif (e.g., a portion of a polypeptide, a domain of a polypeptide, etc.) that comprise one or more residues corresponding to Ala305, Tyr306, Gly307, Asn 308, Gln309, Lys312, Arg342, Lys345, Val346, Val349, Gln375, Arg376, Gln379, Asn380, Leu382, Trp383, Arg386, Asn387, Asp413, Asn415, Val416, Thr418, and Cys419 of SEQ ID NO: 1. In some embodiments, provided agents bind to a motif (e.g., a portion of a polypeptide, a domain of a polypeptide, etc.) that comprise one or more residues corresponding to Ala305, Tyr306, Gly307, Asn 308, Gln309, Lys312, Lys345, Val346, Val349, Gln375, Arg376, Gln379, Asn380, Leu382, Trp383, Arg386, Asn387, Asp413, Asn415, Val416, Thr418, and Cys419 of SEQ ID NO: 1. In some embodiments, an agent binds to a motif comprising one or more of the following residues within SEQ ID NO: 1: Ala305, Tyr306, Gly307, Asn 308, Gln309, Lys312, Arg342, Lys345, Val346, Val349, Gln375, Arg376, Gln379, Asn380, Leu382, Trp383, Arg386, Asn387, Asp413, Asn415, Val416, Thr418, and Cys419. In some embodiments, an agent binds to a motif comprising one or more of the following residues within SEQ ID NO: 1: Ala305, Tyr306, Gly307, Asn 308, Gln309, Lys312, Lys345, Val346, Val349, Gln375, Arg376, Gln379, Asn380, Leu382, Trp383, Arg386, Asn387, Asp413, Asn415, Val416, Thr418, and Cys419. In some embodiments, an agent binds to a motif comprising one or more of the following residues within SEQ ID NO: 1: Ala305, Tyr306, Gly307, Asn 308, Gln309, Lys312, Arg342, Lys345, Val346, Val349, Gln 375, Gln379, Asn380, Leu382, Trp383, Arg386, Asn387, Asp413, Asn415, Val416, Thr418, and Cys419. In some embodiments, an agent binds to a motif comprising one or more of the following residues within SEQ ID NO: 1: Ala305, Tyr306, Gly307, Asn 308, Gln309, Lys312, Lys345, Val346, Val349, Gln379, Asn380, Leu382, Trp383, Arg386, Asn387, Asp413, Asn415, Val416, Thr418, and Cys419. In some embodiments, provided technologies bind to a motif comprising at least 2, 3, 4, 5, or 6 of G307, K312, K345, W383, N387, and N415. In some embodiments, provided technologies bind to a motif comprising at least 2, 3, 4, 5, 6, or 7 of G307, K312, K345, W383, N387, D413, and N415. In some embodiments, provided agents specifically bind to such motifs. In some embodiments, a motif may be referred to as a binding site. In some embodiments, provided technologies selectively bind to such a binding site over an Axin binding site. In some embodiments, provided technologies selectively bind to such a binding site over a Bcl9 binding site. In some embodiments, provided technologies selectively bind to such a binding site over a TCF binding site. In some embodiments, provided technology binds to such a binding site in a reverse N to C direction compared to TCF. In some embodiments, provided technologies do not bind to Axin binding site of beta-catenin. In some embodiments, provided technologies do not bind to Bcl9 binding site of beta-catenin. In some embodiments, provided technologies do not bind to ICAT binding site of beta-catenin. Various technologies, e.g., crystallography, NMR, biochemical assays, etc., may be utilized to assess interactions with beta-catenin Page 6 of 884 12834799v1Attorney Docket Number: 2012675-0389 in accordance with the present disclosure.

[0016] In some embodiments, the provided technology provides an agent, e.g., an agent that is or comprises a stapled peptide. In some embodiments, the number of staples in a staple peptide is 1. In some embodiments, the number of staples in a staple peptide is 2. In some embodiments, the number of staples in a staple peptide is 3. In some embodiments, the number of staples in a staple peptide is 4 or more. In some embodiments, the number of staples in a staple peptide is 4. In some embodiments, a stapled peptide comprises a staple within 2-20 (e.g., 2-10, 3-10, 4-10, 2-7, 3-7, 4-7, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) consecutive amino acids residues. In some embodiments, a stapled peptide comprises two or more staples within 10-20, 10-15, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive amino acids residues. In some embodiments, there are two or more staples within 10 consecutive amino acid residues. In some embodiments, there are two or more staples within 11 consecutive amino acid residues. In some embodiments, there are two or more staples within 12 consecutive amino acid residues. In some embodiments, there are two or more staples within 13 consecutive amino acid residues. In some embodiments, there are two or more staples within 14 consecutive amino acid residues. In some embodiments, there are two or more staples within 15 consecutive amino acid residues. In some embodiments, there are two or more staples within 16 consecutive amino acid residues. In some embodiments, there are two or more staples within 17 consecutive amino acid residues. In some embodiments, there are two or more staples within 18 consecutive amino acid residues. In some embodiments, there are two or more staples within 19 consecutive amino acid residues. In some embodiments, there are two or more staples within 20 consecutive amino acid residues. In some embodiments, two staples are bonded to the same amino acid residue. In some embodiments, two staples are bonded to the same backbone atom. In some embodiments, two staples are bonded to the same backbone carbon atom. In some embodiments, two staples are bonded to an alpha-carbon atom of an amino acid residue, and each independently bonds to another amino acid residue. In some embodiments, the provided technology provides an agent, e.g., an agent that is or comprises a stapled peptide, that comprises three staples within 10-20, 10-15, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive amino acids residues. In some embodiments, there are three or more staples within 10 consecutive amino acid residues. In some embodiments, there are three or more staples within 11 consecutive amino acid residues. In some embodiments, there are three or more staples within 12 consecutive amino acid residues. In some embodiments, there are three or more staples within 13 consecutive amino acid residues. In some embodiments, there are three or more staples within 14 consecutive amino acid residues. In some embodiments, there are three or more staples within 15 consecutive amino acid residues. In some embodiments, there are three or more staples within 16 consecutive amino acid residues. In some embodiments, there are three or more staples within 17 consecutive amino acid residues. In some embodiments, there are three or more staples within 18 consecutive amino acid residues. In some embodiments, there are three or more staples within 19 consecutive amino acid residues. In some Page 7 of 884 12834799v1Attorney Docket Number: 2012675-0389 embodiments, there are three or more staples within 20 consecutive amino acid residues. In some embodiments, two staples are bonded to the same amino acid residue. In some embodiments, two staples are bonded to the same backbone atom. In some embodiments, two staples are bonded to the same backbone carbon atom. In some embodiments, two staples are bonded to an alpha-carbon atom of an amino acid residue, and each independently bonds to another amino acid residue.

[0017] In some embodiments, the provided technology provides an agent, e.g., an agent that is or comprises a stapled peptide, that comprises three staples within 10-20, 10-15, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive amino acids residues. In some embodiments, there are three or more staples within 10 consecutive amino acid residues. In some embodiments, there are three or more staples within 11 consecutive amino acid residues. In some embodiments, there are three or more staples within 12 consecutive amino acid residues. In some embodiments, there are three or more staples within 13 consecutive amino acid residues. In some embodiments, there are three or more staples within 14 consecutive amino acid residues. In some embodiments, there are three or more staples within 15 consecutive amino acid residues. In some embodiments, there are three or more staples within 16 consecutive amino acid residues. In some embodiments, there are three or more staples within 17 consecutive amino acid residues. In some embodiments, there are three or more staples within 18 consecutive amino acid residues. In some embodiments, there are three or more staples within 19 consecutive amino acid residues. In some embodiments, there are three or more staples within 20 consecutive amino acid residues. In some embodiments, two staples are bonded to the same amino acid residue. In some embodiments, two staples are bonded to the same backbone atom. In some embodiments, two staples are bonded to the same backbone carbon atom. In some embodiments, two staples are bonded to an alpha-carbon atom of an amino acid residue, and each independently bonds to another amino acid residue.

[0018] In some embodiments, a first staple in an agent, e.g., an agent that is or comprises a staple peptide, is bonded to amino acid residues at positions i and i+3. In some embodiments, there is a second staple bonded to amino acid residues at positions i+3 and i+10. In some embodiments, there is a third staple bonded to amino acid residues at positions i+9 and i+13. Those skilled in the art appreciate that as used in the art, i, i+3, i+9, i+10, i+13, etc. are routinely utilized to indicate relevant positions of amino acid residues. In some embodiments, they may also indicate absolute positions in an agent, e.g., a peptide. In some embodiments, i is an integer of 1-50 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). In some embodiments, i is 1. In some embodiments, there is a fourth staple in an agent, e.g., a stapled peptide.

[0019] In some embodiments, there are two amino acid residues between two amino acid residues bonded to the same staple. Such a staple may be referred to as a (i, i+3) staple. Similarly, in some embodiments, there are 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues between two amino acid residues bonded to the same staple, and such a staple may be referred to as a (i, i+4), (i, i+5), (i, i+6), (i, i+7), (i, i+8), (i, i+9), (i, i+10), or (i, i+11) staple, respectively. Page 8 of 884 12834799v1Attorney Docket Number: 2012675-0389

[0020] In some embodiments, an agent, e.g., an agent that is or comprises a stapled peptide, comprises a (i, i+2) staple and a (i, i+7) staple. In some embodiments, an agent, e.g., a stapled peptide, comprises a (i, i+3) staple and a (i, i+7) staple. In some embodiments, a (i, i+3) staple and (i, i+7) staple are bonded to the same amino acid residue. In some embodiments, a (i, i+3) staple and (i, i+7) staple bond to the same atom. In some embodiments, a (i, i+3) staple and (i, i+7) staple bond to the same alpha carbon atom. In some embodiments, an agent further comprises a third staple. In some embodiments, a third staple is (i, i+4). In some embodiments, a third staple is (i, i+7). In some embodiments, a third staple is not bonded to any of the amino acid residues that are bonded to the first two staples. In some embodiments, an agent further comprises a fourth staple. In some embodiments, a fourth staple is (i, i+4). In some embodiments, a fourth staple is (i, i+7). In some embodiments, a fourth staple is not bonded to any of the amino acid residues that are bonded to the first two staples. In some embodiments, a fourth staple is not bonded to any of the amino acid residues that are bonded to the first third staples.

[0021] In some embodiments, a provided agent comprises a peptide moiety, e.g., a stapled peptide moiety, that comprises one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) of the following groups (in some embodiments, from the N to C direction): a first acidic group (e.g., of a first acidic amino acid residue); a second acidic group (e.g., of a second acidic amino acid residue); optionally a third acidic group (e.g., of a third acidic amino acid residue); optionally a hydrophobic group (e.g., of a hydrophobic amino acid residue) a first aromatic group (e.g., of a first aromatic amino acid residue); a second aromatic group (e.g., of a first aromatic amino acid residue); and a third aromatic group (e.g., of a third aromatic amino acid residue). In some embodiments, an agent comprises a first and second acidic group and a first, second and third aromatic group. In some embodiments, such an agent additionally comprises a third acidic group (e.g., of a third acid amino acid residue) and / or a hydrophobic group (e.g., of a hydrophobic amino acid residue). In some embodiments, such an agent additionally comprises a third acidic group (e.g., of a third acid amino acid residue) and a hydrophobic group (e.g., of a hydrophobic amino acid residue). In some embodiments, the distance between a first acidic group and a second acidic group is about the distance between the acidic groups of two acidic amino acid residues of a peptide motif, wherein there are two amino acid residues between the two acidic amino acid residues (e.g., if the first acidic amino acid residue is at position N, the second is at position N+3), the distance between a first acidic group and a third acidic group (if present) is about the distance between the acidic groups of two acidic amino acid residues of a peptide motif, wherein there are three amino acid residues between the two acidic amino acid residues (e.g., if the first acidic amino acid residue is at position N, the third is at position N+4), the distance between a first acidic group and a hydrophobic group (if present) is about the distance between the acidic group of an acidic amino acid residue and the hydrophobic group of a hydrophobic amino acid residue of a peptide motif, wherein there are five Page 9 of 884 12834799v1Attorney Docket Number: 2012675-0389 amino acid residues between the first acidic amino acid residue and the hydrophobic amino acid residue (e.g., if the first acidic amino acid residue is at position N, the hydrophobic amino acid residue is at position N+6), the distance between a first acidic group and a first aromatic group is about the distance between the acidic group of a first acidic amino acid residue and the aromatic group of an aromatic amino acid residue of a peptide motif, wherein there are six amino acid residues between the first acidic amino acid residue and the first aromatic amino acid residue (e.g., if the first acidic amino acid residue is at position N, the first aromatic amino acid residue is at position N+7), the distance between the first aromatic group and the second aromatic group is about the distance between the aromatic groups of two aromatic amino acid residues of a peptide motif, wherein there are two amino acid residues between the two aromatic amino acid residues (e.g., if the first aromatic amino acid residue is at position M, the second is at position M+3), and / or the distance between the first aromatic group and the third aromatic group is about the distance between the aromatic groups of two aromatic amino acid residues of a peptide motif, wherein there are three amino acid residues between the two aromatic amino acid residues (e.g., if the first aromatic amino acid residue is at position M, the third is at position M+4). In some embodiments, a first acidic amino acid residue is at position N, a second acidic amino acid residue is at position N+3, and a first, second and third aromatic amino acid residue are at positions N+7, N+10 and N+11, respectively. In some embodiments, a first acidic amino acid residue is at position N, a second acidic amino acid residue is at position N+3, a third acidic amino acid residue is at position N+4, and a first, second and third aromatic amino acid residue are at positions N+7, N+10 and N+11, respectively. In some embodiments, a first acidic amino acid residue is at position N, a second acidic amino acid residue is at position N+3, a hydrophobic amino acid residue is at position N+6, and a first, second and third aromatic amino acid residue are at positions N+7, N+10 and N+11, respectively. In some embodiments, a first acidic amino acid residue is at position N, a second acidic amino acid residue is at position N+3, a third acidic amino acid residue is at position N+4, a hydrophobic amino acid residue is at position N+6, and a first, second and third aromatic amino acid residue are at positions N+7, N+10 and N+11, respectively. In some embodiments, M is N+7. In some embodiments, N is 1-7. In some embodiments, N is 1, 2, 3, 4, or 5. In some embodiments, N is 1. In some embodiments, N is 2. In some embodiments, N is 3. In some embodiments, N is 4. In some embodiments, N is 5. In some embodiments, M is 8-16. In some embodiments, M is 8. In some embodiments, M is 9. In some embodiments, M is 10. In some embodiments, M is 11. In some embodiments, M is 12. In some embodiments, M is 13. In some embodiments, a peptide motif is an alpha-helical motif wherein each amino acid residue is independently an alpha amino acid residue. In some embodiments, a peptide motif is stapled. In some embodiments, there are two or more staples in a peptide motif; in some embodiments, there are three; in some embodiments, there are four; in some embodiments, there are four or more. In some embodiments, a first acidic group is of X2as described herein, a second acidic group is of X5as described herein, a third acidic group (if present) is of X6as described herein, a hydrophobic group (if present) is of X8as described herein, a first aromatic group is of X9as described herein, a second aromatic group is of X12as described herein, and / or a third aromatic group is of X13as described herein. In some Page 10 of 884 12834799v1Attorney Docket Number: 2012675-0389 embodiments, as described herein, a provided agent is a stapled peptide comprising one or more staples. In some embodiments, as described herein, a provided agent is a stapled peptide comprising two or more staples. In some embodiments, as described herein, a provided agent is a stapled peptide comprising three or more staples. In some embodiments, when contacted with a beta-catenin polypeptide, a first acidic group interacts with Lys312 and / or Gly307 or amino acid residues corresponding thereto, a second acidic group interacts with Asn387, Trp383 and / or Arg386 or amino acid residues corresponding thereto, a first aromatic group interacts with Lys345 and / or Trp383 or amino acid residues corresponding thereto, a second aromatic group interacts with Trp383 and / or Asn415 or amino acid residues corresponding thereto, and a third aromatic group interacts with Gln379, Leu383, Val416, Asn415 and / or Trp383 or amino acid residues corresponding thereto. In some embodiments, a third acidic group interacts with Asn387, Trp383 and / or Arg386 or amino acid residues corresponding thereto. In some embodiments, a hydrophobic group interacts with Trp383 or an amino acid residue corresponding thereto.

[0022] In some embodiments, a target binding moiety is –[PTBM], wherein PTBMis or comprises a peptide, e.g., a stapled peptide. In some embodiments, PTBMis a peptide. In some embodiments, PTBMis or comprises a stapled peptide. In some embodiments, PTBMcomprises a stapled peptide. In some embodiments, PTBMis a stapled peptide.

[0023] In some embodiments, a peptide, e.g., PTBM, has the structure of formula I: RN−LP1−LAA1−LP2−LAA2−LP3−LAA3−LP4−LAA4−LP5−LAA5−LP6−LAA6−LP7−RC, Ior a salt thereof, wherein each variable is independently as described herein.

[0024] In some embodiments, a peptide, e.g., PTBM, is or comprises a peptide comprising: [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17[X18]p18, wherein: each of p0, p15, p16, p17 and p18 is independently 0 or 1; each of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17and X18is independently an amino acid residue.

[0025] In some embodiments, a peptide, e.g., PTBM, is or comprises a peptide comprising: [X]pX1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17[X18]p18 [X]p’, wherein: each of p15, p16, p17 and p18 is independently 0 or 1; each of p and p’ is independently 0-10; each of X, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17and X18is independently an amino acid residue.

[0026] In some embodiments, a peptide, e.g., PTBM, is or comprises RN−[X]pX1X2X3X4X5X6X7X8X9X10X11X12X13[X14]p14[X15]p15[X16]p16[X17]p17[X18]p18[X]p’−RC, wherein each variable is independently as described herein. Page 11 of 884 12834799v1Attorney Docket Number: 2012675-0389

[0027] In some embodiments, a peptide, e.g., PTBM, is or comprises X1X2X3X4X5X6X7X8X9X10X11X12X13[X14]p14[X15]p15[X16]p16[X17]p17[X18]p18[X19]p19[X20]p20[X21]p21[X22]p22[X23]p23, wherein each of p14, p15, p16, p17, p18, p19, p20, p21, p22, and p23 is independently 0 or 1, and each of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, and X23is independently an amino acid residue as described herein.

[0028] In some embodiments, such a peptide comprises three or more staples. In some embodiments, such a peptide comprises five or more residues suitable for stapling.

[0029] In some embodiments, a peptide, e.g., PTBM, is or comprises a peptide comprising: [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17[X18]p18, wherein: each of p0, p15, p16, p17 and p18 is independently 0 or 1; each of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17and X18is independently an amino acid residue, wherein: X2comprises a side chain comprising an acidic or a polar group; X5comprises a side chain comprising an acidic or a polar group; X13comprises a side chain comprising an optionally substituted aromatic group; and two or more of X1, X3, X4, X7, X10, X11and X14are each independently an amino acid residue suitable for stapling, or are each independently stapled.

[0030] In some embodiments, a peptide, e.g., PTBM, is or comprises a peptide comprising: [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17[X18]p18, wherein: each of p0, p15, p16, p17 and p18 is independently 0 or 1; each of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17and X18is independently an amino acid residue, wherein: X2comprises a side chain comprising an acidic or a polar group; X5comprises a side chain comprising an acidic or a polar group; X6comprises a side chain comprising an acidic or a polar group; X13comprises a side chain comprising an optionally substituted aromatic group; and two or more of X1, X3, X4, X7, X10, X11and X14are each independently an amino acid residue suitable for stapling, or are each independently stapled.

[0031] In some embodiments, an agent is or comprises a peptide. In some embodiments, an agent is or comprises a stapled peptide. In some embodiments, an agent is a peptide. In some embodiments, an agent is a stapled peptide. In some embodiments, an agent, a peptide, or a stapled peptide has the structure of [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17[X18]p18. In some embodiments, X1and X4, and / or X4and X11are independently amino acid residues suitable for stapling, or are stapled, or X3and X10independently amino acid residues suitable for stapling, or are stapled. In some embodiments, X1and X4Page 12 of 884 12834799v1Attorney Docket Number: 2012675-0389 are independently amino acid residues suitable for stapling. In some embodiments, X1and X4are stapled. In some embodiments, X4and X11are independently amino acid residues suitable for stapling. In some embodiments, X4and X11are stapled. In some embodiments, X1and X4, and X4and X11are independently amino acid residues suitable for stapling. In some embodiments, a stapled peptide is a stitched peptide comprising two or more staples, some of which may bond to the same backbone atom. In some embodiments,X1and X4are stapled, and X4and X11are stapled. In some embodiments, a staple connecting X1and X4and a staple connecting X4and X11are bonded to a common backbone atom of X4. In some embodiments, a common backbone atom is the alpha-carbon of X4. In some embodiments, X3and X10are independently amino acid residues suitable for stapling. In some embodiments, X3and X10are stapled. In some embodiments, X1and X3are independently amino acid residues suitable for stapling. In some embodiments, X1and X3are stapled. In some embodiments, X10and X14are independently amino acid residues suitable for stapling. In some embodiments, X10and X14are stapled. In some embodiments, X7and X10are independently amino acid residues suitable for stapling. In some embodiments, X7and X10are stapled. In some embodiments, X7and X14are independently amino acid residues suitable for stapling. In some embodiments, X7and X14are stapled. In some embodiments, X3and X7are independently amino acid residues suitable for stapling. In some embodiments, X3and X7are stapled.

[0032] In some embodiments, the present disclosure provides an agent comprising an E3 ubiquitin ligase binding moiety. In some embodiments, LBM is an E3 ubiquitin ligase binding moiety. Various E3 ubiquitin ligase binding moieties are reported and can be utilized in accordance with the present disclosure. RRAnA

[0033] In some embodiments, LBM i , wherein each variable is independently as described herein. In som, (RRC)nC (RRD)nD, wherein each variable is independently as describedPage 13 of 884 12834799v1Attorney Docket Number: 2012675-0389 RIVH O N H N herein. In some embodiments , wherein each variable is independently as described herein. In some eLE(RRF)nF LEFE y as ch(RRL)nL L , wherein each variable is independently as described herein. InH O N some embodiments, isO n some embodiments, such LBM can bind to an E3 ubiquitin ligase., present disclosure provides agents that can bind to a polypeptide comprising or consisting of residues 305-419 of SEQ ID NO: 1 as described herein. In some embodiments, an agent has a molecular mass of no more than about 5000 Daltons. In some embodiments, it is no more than Page 14 of 884 12834799v1Attorney Docket Number: 2012675-0389 about 2500, 3000, 3500, 4000, 4500 or 5000 Daltons. In some embodiments, it is no more than about 2500 Daltons. In some embodiments, it is no more than about 3000 Daltons. In some embodiments, it is no more than about 3500 Daltons. In some embodiments, it is no more than about 4000 Daltons. In some embodiments, it is no more than about 500 Daltons.

[0035] In some embodiments, the present disclosure provides various technologies, e.g., reagents methods, etc., for preparing, characterizing, assessing and using provided agents and compositions thereof. In some embodiments, the present disclosure provides, e.g., methods, reagents and / or systems for identifying, characterizing and / or assessing provided agents and use thereof (e.g., as therapeutic or diagnostic agents).

[0036] In some embodiments, the present disclosure provides pharmaceutical compositions comprising or delivering a provided agent and a pharmaceutical acceptable carrier. In some embodiments, a provided agent is in a pharmaceutically acceptable salt form. In some embodiments, a composition comprises a pharmaceutically acceptable salt form an agent. In some embodiments, in various compositions and methods, agents are provided as pharmaceutically acceptable salt forms.

[0037] In some embodiments, the present disclosure provides methods for modulating a level, property, activity and / or function of beta-catenin, comprising contacting beta-catenin with a provided agent. In some embodiments, the present disclosure provides methods for modulating a level, property, activity and / or function of beta-catenin in a system comprising beta-catenin, comprising administering to a system an effective amount of a provided agent. In some embodiments, the present disclosure provides methods for modulating a level, property, activity and / or function of beta-catenin in a system expressing beta-catenin, comprising administering or delivering to a system an effective amount of a provided agent. In some embodiments, a level of beta-catenin is reduced. In some embodiments, an activity of beta-catenin is inhibited or reduced. In some embodiments, a function of beta-catenin is inhibited or reduced. In some embodiments, a property, activity and / or function is associated with beta-catenin / TCF interaction.

[0038] In some embodiments, the present disclosure provides methods for modulating beta-catenin / TCF interaction. In some embodiments, the present disclosure provides methods for modulating beta-catenin / TCF interaction, comprising contacting beta-catenin with a provided agent. In some embodiments, the present disclosure provides methods for modulating beta-catenin / TCF interaction in a system comprising beta-catenin and TCF, comprising administering or delivering to the system an effective amount a provided agent. In some embodiments, the present disclosure provides methods for modulating beta-catenin / TCF interaction in a system expressing beta-catenin and TCF, comprising administering or delivering to the system an effective amount a provided agent. In some embodiments, interaction between beta-catenin and TCF is reduced. In some embodiments, interaction between beta-catenin and TCF is inhibited.

[0039] In some embodiments, the present disclosure provides methods for modulating beta-catenin and E3 ubiquitin ligase interaction. In some embodiments, the present disclosure provides methods for modulating beta-catenin and E3 ubiquitin ligase interaction, comprising contacting beta-catenin with a provided agent. In some embodiments, the present disclosure provides methods for modulating beta-catenin Page 15 of 884 12834799v1Attorney Docket Number: 2012675-0389 and E3 ubiquitin ligase interaction in a system comprising beta-catenin and an E3 ubiquitin ligase, comprising administering or delivering to the system an effective amount a provided agent. In some embodiments, the present disclosure provides methods for modulating beta-catenin and E3 ubiquitin ligase interaction in a system expressing beta-catenin and an E3 ubiquitin ligase, comprising administering or delivering to the system an effective amount a provided agent. In some embodiments, interaction between beta-catenin and an E3 ubiquitin ligase is increased. In some embodiments, interactions between beta-catenin and an E3 ubiquitin ligase is promoted.

[0040] In some embodiments, the present disclosure provides methods for inducing degradation of beta- catenin. In some embodiments, the present disclosure provides methods for inducing degradation of beta- catenin, comprising contacting beta-catenin with a provided agent. In some embodiments, the present disclosure provides methods for inducing degradation of beta-catenin in a system comprising beta-catenin and an E3 ubiquitin ligase, comprising administering or delivering to the system an effective amount a provided agent. In some embodiments, the present disclosure provides methods for inducing degradation of beta-catenin in a system expressing beta-catenin and an E3 ubiquitin ligase, comprising administering or delivering to the system an effective amount a provided agent. In some embodiments, the rate of beta-catenin degradation in a system is increased. In some embodiments, levels of beta-catenin in a system are reduced.

[0041] In some embodiments, the present disclosure provides methods for increasing beta-catenin ubiquitination. In some embodiments, the present disclosure provides methods for increasing beta-catenin ubiquitination, comprising contacting beta-catenin with a provided agent. In some embodiments, the present disclosure provides methods for increasing beta-catenin ubiquitination in a system comprising beta-catenin and an E3 ubiquitin ligase, comprising administering or delivering to the system an effective amount a provided agent. In some embodiments, the present disclosure provides methods for increasing beta-catenin ubiquitination in a system expressing beta-catenin and an E3 ubiquitin ligase, comprising administering or delivering to the system an effective amount a provided agent.

[0042] In some embodiments, the present disclosure provides methods for reducing beta-catenin levels. In some embodiments, the present disclosure provides methods for reducing beta-catenin level, comprising contacting beta-catenin with a provided agent. In some embodiments, the present disclosure provides methods for reducing beta-catenin level in a system comprising beta-catenin and an E3 ubiquitin ligase, comprising administering or delivering to the system an effective amount a provided agent. In some embodiments, the present disclosure provides methods for reducing beta-catenin level in a system expressing beta-catenin and an E3 ubiquitin ligase, comprising administering or delivering to the system an effective amount a provided agent.

[0043] In some embodiments, the present disclosure provides methods for inhibiting cell proliferation, comprising administering or delivering to a population of cells an effective amount of a provided agent. In some embodiments, the present disclosure provides methods for inhibiting cell proliferation in a system, comprising administering or delivering to the system an effective amount of a provided agent. In some Page 16 of 884 12834799v1Attorney Docket Number: 2012675-0389 embodiments, the present disclosure provides methods for inhibiting cell growth, comprising administering or delivering to a population of cells an effective amount of a provided agent. In some embodiments, the present disclosure provides methods for inhibiting cell growth in a system, comprising administering or delivering to the system an effective amount of a provided agent. In some embodiments, such cell proliferation is beta-catenin dependent. In some embodiments, such cell growth is beta-catenin dependent. In some embodiments, such proliferation or growth is dependent on beta-catenin interactions with TCF.

[0044] In some embodiments, the present disclosure provides methods for reducing or preventing activation of a WNT pathway. In some embodiments, the present disclosure provides methods for reducing or preventing activation of a WNT pathway in a system, comprising administering or delivering to the system an effective amount of a provided agent.

[0045] In some embodiments, a system is in vitro. In some embodiments, a system is ex vivo. In some embodiments, a system is in vivo. In some embodiments, a system is or comprise a cell. In some embodiments, a system is or comprises a tissue. In some embodiments, a system is or comprises an organ. In some embodiments, a system is or comprises an organism. In some embodiments, a system is an animal. In some embodiments, a system is human. In some embodiments, a system is or comprises cells, tissues or organs associated with a condition, disorder or disease. In some embodiments, a system is or comprises cancer cells.

[0046] In some embodiments, the present disclosure provides methods for preventing conditions, disorders or diseases. In some embodiments, the present disclosure provides methods for reducing risks of conditions, disorders or diseases. In some embodiments, the present disclosure provides methods for preventing a condition, disorder or disease, comprising administering or delivering to a subject susceptible thereto an effective amount of an agent of the present disclosure. In some embodiments, the present disclosure provides methods for reducing risk of a condition, disorder or disease, comprising administering or delivering to a subject susceptible thereto an effective amount of an agent of the present disclosure. In some embodiments, the present disclosure provides methods for reducing risks of a condition, disorder or disease in a population, comprising administering or delivering to a population of subjects susceptible thereto an effective amount of an agent of the present disclosure. In some embodiments, the present disclosure provides methods for treating conditions, disorders or diseases. In some embodiments, the present disclosure provides methods for treating a condition, disorder or disease, comprising administering or delivering to a subject suffering therefrom an effective amount of an agent of the present disclosure. In some embodiments, a symptom is reduced, removed or prevented. In some embodiments, one or more parameters for assessing a condition, disorder or disease are improved. In some embodiments, survival of subjects are extended. As appreciated by those skilled in the art, in some embodiments, prevention, reduced risks, and / or effects of treatment may be assessed through clinical trials and may be observed in subject populations. In some embodiments, a condition, disorder or disease is cancer. In some embodiments, a condition, disorder or disease is associated with beta-catenin. In some embodiments, a condition, disorder or disease is associated Page 17 of 884 12834799v1Attorney Docket Number: 2012675-0389 with beta-catenin interaction with TCF. In some embodiments, a condition, disorder or disease is associated with beta-catenin interaction another agent, e.g., another polypeptide. In some embodiments, a condition, disorder or disease is bladder cancer. In some embodiments, a condition, disorder or disease is endometrial cancer. In some embodiments, a condition, disorder or disease is adrenocortical carcinoma. In some embodiments, a condition, disorder or disease is gastric cancer. In some embodiments, a condition, disorder or disease is lung cancer. In some embodiments, a condition, disorder or disease is melanoma. In some embodiments, a condition, disorder or disease is esophageal cancer. In some embodiments, a condition, disorder or disease is colorectal cancer. In some embodiments, a cancer is liver cancer. In some embodiments, a cancer is prostate cancer. In some embodiments, a cancer is breast cancer. In some embodiments, a cancer is endometrial cancer. Mutations that lead to constitutive activation of Wnt / beta- catenin-mediated signaling are reported to be present in approximately 20% of all human cancers. In some embodiments, a condition, disorder or disease is associated with WNT signaling. In some embodiments, a condition, disorder or disease is associated with beta-catenin dependent WNT signaling. In some embodiments, a condition, disorder or disease is associated with beta-catenin / TCF interaction. In some embodiments, it has been reported that beta-catenin / TCFs interactions may promote cell proliferation, epithelial-mesenchymal transition (EMT), a cancer stem cell phenotype, etc.

[0047] In some embodiments, agents are administered as pharmaceutically compositions that comprise or deliver such agents. In some embodiments, agents are provided and / or delivered in pharmaceutically acceptable salt forms. In some embodiments, in a composition (e.g., a liquid composition of certain pH) an agent may exist in various forms including various pharmaceutically acceptable salt forms.

[0048] In some embodiments, a provided agent is utilized in combination with a second therapy. In some embodiments, a provided agent is utilized in combination with a second therapeutic agent. In some embodiments, a second therapy or therapeutic agent is administered prior to an administration or delivery of a provided agent. In some embodiments, a second therapy or therapeutic agent is administered at about the same time as an administration or delivery of a provided agent. In some embodiments, a second therapy or therapeutic agent is administered subsequently to an administration or delivery of a provided agent. In some embodiments, a subject is exposed to both a provided agent and a second therapeutic agent. In some embodiments, a subject is exposed to a therapeutic effect of a provided agent and a therapeutic effect of a second therapeutic agent. In some embodiments, a second therapy is or comprises surgery. In some embodiments, a second therapy is or comprises radiation therapy. In some embodiments, a second therapy is or comprises immunotherapy. In some embodiments, a second therapeutic agent is or comprises a drug. In some embodiments, a second therapeutic agent is or comprises a cancer drug. In some embodiments, a second therapeutic agent is or comprises a chemotherapeutic agent. In some embodiments, a second therapeutic agent is or comprises a hormone therapy agent. In some embodiments, a second therapeutic agent is or comprises a kinase inhibitor. In some embodiments, a second therapeutic agent is or comprises a checkpoint inhibitor (e.g., antibodies against PD-1, PD-L1, CTLA-4, etc.). In some embodiments, a provide Page 18 of 884 12834799v1Attorney Docket Number: 2012675-0389 agent can be administered with lower unit dose and / or total dose compared to being used alone. In some embodiments, a second agent can be administered with lower unit dose and / or total dose compared to being used alone. In some embodiments, one or more side effects associated with administration of a provided agent and / or a second therapy or therapeutic agent are reduced. In some embodiments, a combination therapy provides improved results, e.g., when compared to each agent utilized individually. In some embodiments, a combination therapy achieves one or more better results, e.g., when compared to each agent utilized individually.

[0049] Further description of certain embodiments of provided technologies is presented below. BRIEF DESCRIPTION OF THE DRAWING

[0050] Figure 1. Provided technologies can provide useful pharmacokinetic profiles. Plasma levels of various agents after single IV dose are provided as examples. From left to right, in pairs of timepoints as indicated: Agent 2294, 15 mg / kg; Agent 2317, 15 mg / kg; Agent 2326, 15 mg / kg; I-66, 50 mg / kg; Agent 2410, 15 mg / kg; Agent 3145, 15 mg / kg; Agent 2293, 15 mg / kg. Assessments were performed in NU / J male mice with COLO320DM SC (subcutaneous) tumor model. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9. N=3 mice / timepoint, all data shown as mean ± S.D.

[0051] Figure 2. Provided technologies can provide useful pharmacokinetic profiles. Tumor levels of various agents after single IV dose are provided as examples. From left to right, in pairs of timepoints as indicated: Agent 2294, 15 mg / kg; Agent 2317, 15 mg / kg; Agent 2326, 15 mg / kg; I-66, 50 mg / kg; Agent 2410, 15 mg / kg; Agent 3145, 15 mg / kg; Agent 2293, 15 mg / kg. Assessments were performed in NU / J male mice with COLO320DM SC tumor model. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L- arginine, pH 8-9. N=3 mice / timepoint, all data shown as mean ± S.D.

[0052] Figure 3. Provided technologies can reduce levels of beta-catenin polypeptides in vivo. From left to right, in pairs of timepoints as indicated: vehicle, Agent 2294, 15 mg / kg; Agent 2317, 15 mg / kg; Agent 2326, 15 mg / kg; I-66, 50 mg / kg; Agent 2410, 15 mg / kg; Agent 3145, 15 mg / kg; Agent 2293, 15 mg / kg. Single IV dose. Assessments were performed by western blot of tumor samples taken from NU / J male mice with COLO320DM SC tumor model. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9. N=3 mice / timepoint, all data shown as mean ± S.D.

[0053] Figure 4. Provided technologies can reduce levels of beta-catenin polypeptides in vivo without dramatic reduction of CTNNB1 mRNA levels. From left to right, in pairs of timepoints as indicated: vehicle, Agent 2294, 15 mg / kg; Agent 2317, 15 mg / kg; Agent 2326, 15 mg / kg; I-66, 50 mg / kg; Agent 2410, 15 mg / kg; Agent 3145, 15 mg / kg; Agent 2293, 15 mg / kg. Single IV dose. Assessments were performed by qPCR in tumor samples taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9. N=3 mice / timepoint, all data shown as mean ± S.D.

[0054] Figure 5. Provided technologies can reduce levels of AXIN2 mRNA levels in vivo. From left to Page 19 of 884 12834799v1Attorney Docket Number: 2012675-0389 right, in pairs of timepoints as indicated: vehicle, Agent 2294, 15 mg / kg; Agent 2317, 15 mg / kg; Agent 2326, 15 mg / kg; I-66, 50 mg / kg; Agent 2410, 15 mg / kg; Agent 3145, 15 mg / kg; Agent 2293, 15 mg / kg. Single IV dose. Assessments were performed by qPCR in tumor samples taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9. N=3 mice / timepoint, all data shown as mean ± S.D.

[0055] Figure 6. Provided technologies can provide useful pharmacokinetic profiles. Plasma levels of various agents after single IV doses of each agent are as examples. From left to right, in pairs of timepoints as indicated: Agent 2317, 15 mg / kg; Agent 2313, 15 mg / kg; Agent 2315, 15 mg / kg; Agent 2359, 15 mg / kg; Agent 2387, 15 mg / kg; Agent 2310, 15 mg / kg. Assessments were performed on samples taken from NU / J male mice with COLO320DM SC tumor model. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L- arginine, pH 8-9. N=3 mice / timepoint, all data shown as mean ± S.D.

[0056] Figure 7. Provided technologies can provide useful pharmacokinetic profiles. Tumor levels of various agents after single IV doses of each agent are provided as examples. From left to right, in pairs of timepoints as indicated: Agent 2317, 15 mg / kg; Agent 2313, 15 mg / kg; Agent 2315, 15 mg / kg; Agent 2359, 15 mg / kg; Agent 2387, 15 mg / kg; Agent 2310, 15 mg / kg. Assessments were performed in tumor samples taken from NU / J male mice with COLO320DM SC tumor model. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9. N=3 mice / timepoint, all data shown as mean ± S.D.

[0057] Figure 8. Provided technologies can reduce levels of beta-catenin polypeptides in vivo. From left to right, in pairs of timepoints as indicated: vehicle, Agent 2317, 15 mg / kg; Agent 2313, 15 mg / kg; Agent 2315, 15 mg / kg; Agent 2359, 15 mg / kg; Agent 2387, 15 mg / kg; Agent 2310, 15 mg / kg. Single IV dose. Assessments were performed by western blot of tumor samples taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9. N=3 mice / timepoint, all data shown as mean ± S.D.

[0058] Figure 9. Provided technologies can reduce levels of AXIN2 mRNA levels in vivo. From left to right, in pairs of timepoints as indicated: vehicle, Agent 2317, 15 mg / kg; Agent 2313, 15 mg / kg; Agent 2315, 15 mg / kg; Agent 2359, 15 mg / kg; Agent 2387, 15 mg / kg; Agent 2310, 15 mg / kg. Single IV dose. Assessments were performed by qPCR in tumor samples taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9. N=3 mice / timepoint, all data shown as mean ± S.D.

[0059] Figure 10. Provided technologies can increase CXCL12 mRNA levels in vivo. From left to right, in pairs of timepoints as indicated: vehicle, Agent 2317, 15 mg / kg; Agent 2313, 15 mg / kg; Agent 2315, 15 mg / kg; Agent 2359, 15 mg / kg; Agent 2387, 15 mg / kg; Agent 2310, 15 mg / kg. Single IV dose. Assessments were performed by qPCR in tumor samples taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9. N=3 mice / timepoint, all data shown as mean ± S.D.

[0060] Figure 11. Provided technologies can reduce levels of MYCN mRNA levels in vivo. From left to Page 20 of 884 12834799v1Attorney Docket Number: 2012675-0389 right, in pairs of timepoints as indicated: vehicle, Agent 2317, 15 mg / kg; Agent 2313, 15 mg / kg; Agent 2315, 15 mg / kg; Agent 2359, 15 mg / kg; Agent 2387, 15 mg / kg; Agent 2310, 15 mg / kg. Single IV dose. Assessments were performed by qPCR in tumor samples taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9. N=3 mice / timepoint, all data shown as mean ± S.D.

[0061] Figure 12. Provided technologies can provide useful pharmacokinetic profiles. From left to right: Agent 2313, Agent 2440, Agent 2445, Agent 2446, Agent 2448, Agent 2479, Agent 2484, Agent 2416, Agent 2341, Agent 2330, Agent 2347, Agent 2548, and Agent 2316. Single IV dose. Tumor samples were taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously at a dosage of 15 mg / kg. Assessments were performed at 96 h after administration of agent. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9. N=3 mice, all data shown as mean ± S.D.

[0062] Figure 13. Provided technologies can provide useful pharmacokinetic profiles. From left to right: Agent 2313, Agent 2440, Agent 2445, Agent 2446, Agent 2448, Agent 2479, Agent 2484, Agent 2416, Agent 2341, Agent 2330, Agent 2347, Agent 2548, and Agent 2316. Single IV dose. Plasma samples were taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously at a dosage of 15 mg / kg. Assessments were performed at 96 h after administration of agent. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9. N=3 mice, all data shown as mean ± S.D.

[0063] Figure 14. Provided technologies can reduce levels of beta-catenin polypeptides in vivo. From left to right: Agent 2313, Agent 2440, Agent 2445, Agent 2446, Agent 2448, Agent 2479, Agent 2484, Agent 2416, Agent 2341, Agent 2330, Agent 2347, Agent 2548, and Agent 2316. Single IV dose. Assessments were performed by western blot of tumor samples taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously at a dosage of 15 mg / kg. Assessments were performed at 96 h after administration of agent. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9. N=3 mice, all data shown as mean ± S.D.

[0064] Figure 15. Provided technologies can reduce levels of AXIN2 mRNA levels in vivo. From left to right: Agent 2313, Agent 2440, Agent 2445, Agent 2446, Agent 2448, Agent 2479, Agent 2484, Agent 2416, Agent 2341, Agent 2330, Agent 2347, Agent 2548, and Agent 2316. Single IV dose. Assessments were performed by qPCR in tumor samples taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously at a dosage of 15 mg / kg. Assessments were performed at 96 h after administration of agent. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9. N=3 mice, all data shown as mean ± S.D.

[0065] Figure 16. Provided technologies can provide useful pharmacokinetic and pharmacodynamic profiles in vivo. From left to right: Agent 2423 (IV-15 mpk), Agent 2340 (IV-15 mpk), Agent 2418 (IV-15 mpk), Agent 2362 (IV-15 mpk), Agent 2572 (IV-15 mpk), Agent 2552 (IV-15 mpk), Agent 2668 (IV-15 mpk), Agent 2670 (IV-15 mpk), Agent 2317 (IV-15 mpk), Agent 2425 (IV-15 mpk), Agent 2410 (IV-15 mpk), Agent 2410 (SC-15 mpk), Agent 2410 (SC-30 mpk). For each agent, provided are levels of the agent in Page 21 of 884 12834799v1Attorney Docket Number: 2012675-0389 tumor (left, in µg / g), levels of beta-catenin polypeptide (center, in percent relative to vehicle), and levels of AXIN2 mRNA (right, in percent relative to vehicle). Assessments of beta-catenin polypeptide levels were performed by western blot of tumor samples. Assessments of AXIN2 mRNA levels were performed by qPCR in tumor samples. Tumor samples were taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously at a dosage of 15 mg / kg (IV-15 mpk), or subcutaneously at a dosage of 15 mg / kg (SC-15 mpk) or 30 mg / kg (SC-30 mpk). Single dose. Assessments were performed at 96 h after administration of agent. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9 for intravenous administration and 30 mM tris buffer pH 10.5-11 for subcutaneous administration. N=3 mice, all data shown as mean ± S.D.

[0066] Figure 17. Provided technologies can provide useful pharmacokinetic profiles. From left to right: Agent 2423 (IV-15 mpk), Agent 2340 (IV-15 mpk), Agent 2418 (IV-15 mpk), Agent 2362 (IV-15 mpk), Agent 2572 (IV-15 mpk), Agent 2552 (IV-15 mpk), Agent 2668 (IV-15 mpk), Agent 2670 (IV-15 mpk), Agent 2317 (IV-15 mpk), Agent 2425 (IV-15 mpk), Agent 2410 (IV-15 mpk), Agent 2410 (SC-15 mpk), Agent 2410 (SC-30 mpk). Tumor samples were taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously at a dosage of 15 mg / kg (IV-15 mpk), or subcutaneously at a dosage of 15 mg / kg (SC-15 mpk) or 30 mg / kg (SC-30 mpk). Single dose. Assessments were performed at 96 h after administration of agent. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9 for intravenous administration and 30 mM tris buffer pH 10.5-11 for subcutaneous administration. N=3 mice, all data shown as mean ± S.D.

[0067] Figure 18. Provided technologies can provide useful pharmacokinetic profiles. From left to right: Agent 2423 (IV-15 mpk), Agent 2340 (IV-15 mpk), Agent 2418 (IV-15 mpk), Agent 2362 (IV-15 mpk), Agent 2572 (IV-15 mpk), Agent 2552 (IV-15 mpk), Agent 2668 (IV-15 mpk), Agent 2670 (IV-15 mpk), Agent 2317 (IV-15 mpk), Agent 2425 (IV-15 mpk), Agent 2410 (IV-15 mpk), Agent 2410 (SC-15 mpk), Agent 2410 (SC-30 mpk). Plasma samples were taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously at a dosage of 15 mg / kg (IV-15 mpk), or subcutaneously at a dosage of 15 mg / kg (SC-15 mpk) or 30 mg / kg (SC-30 mpk). Single dose. Assessments were performed at 96 h after administration of agent. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9 for intravenous administration and 30 mM tris buffer pH 10.5-11 for subcutaneous administration. N=3 mice, all data shown as mean ± S.D.

[0068] Figure 19. Provided technologies can reduce levels of beta-catenin polypeptides in vivo. From left to right: Vehicle, Agent 2423 (IV-15 mpk), Agent 2340 (IV-15 mpk), Agent 2418 (IV-15 mpk), Agent 2362 (IV-15 mpk), Agent 2572 (IV-15 mpk), Agent 2552 (IV-15 mpk), Agent 2668 (IV-15 mpk), Agent 2670 (IV-15 mpk), Agent 2317 (IV-15 mpk), Agent 2410 (IV-15 mpk), and Agent 2425 (IV-15 mpk). Assessments were performed by western blot of tumor samples taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously at a dosage of 15 mg / kg. Single dose. Assessments were performed at 96 h after administration of agent. Vehicle was 10% w / w DMSO in 30 mM Page 22 of 884 12834799v1Attorney Docket Number: 2012675-0389 tris, 5 mg / mL L-arginine, pH 8-9. N=3 mice, all data shown as mean ± S.D.

[0069] Figure 20. Provided technologies can reduce levels of AXIN2 mRNA levels in vivo. From left to right: Agent 2423 (IV-15 mpk), Agent 2340 (IV-15 mpk), Agent 2418 (IV-15 mpk), Agent 2362 (IV-15 mpk), Agent 2572 (IV-15 mpk), Agent 2552 (IV-15 mpk), Agent 2668 (IV-15 mpk), Agent 2670 (IV-15 mpk), Agent 2317 (IV-15 mpk), Agent 2425 (IV-15 mpk), Agent 2410 (IV-15 mpk), Agent 2410 (SC-15 mpk), Agent 2410 (SC-30 mpk). Assessments were performed by qPCR in tumor samples taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously at a dosage of 15 mg / kg (IV-15 mpk), or subcutaneously at a dosage of 15 mg / kg (SC-15 mpk) or 30 mg / kg (SC-30 mpk). Single dose. Assessments were performed at 96 h after administration of agent. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9 for intravenous administration and 30 mM tris buffer pH 10.5-11 for subcutaneous administration. N=3 mice, all data shown as mean ± S.D.

[0070] Figure 21. Provided technologies can reduce levels of MYCN mRNA levels in vivo. From left to right: Agent 2423 (IV-15 mpk), Agent 2340 (IV-15 mpk), Agent 2418 (IV-15 mpk), Agent 2362 (IV-15 mpk), Agent 2572 (IV-15 mpk), Agent 2552 (IV-15 mpk), Agent 2668 (IV-15 mpk), Agent 2670 (IV-15 mpk), Agent 2317 (IV-15 mpk), Agent 2425 (IV-15 mpk), Agent 2410 (IV-15 mpk), Agent 2410 (SC-15 mpk), Agent 2410 (SC-30 mpk). Assessments were performed by qPCR in tumor samples taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously at a dosage of 15 mg / kg (IV-15 mpk), or subcutaneously at a dosage of 15 mg / kg (SC-15 mpk) or 30 mg / kg (SC-30 mpk). Single dose. Assessments were performed at 96 h after administration of agent. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9 for intravenous administration and 30 mM tris buffer pH 10.5-11 for subcutaneous administration. N=3 mice, all data shown as mean ± S.D.

[0071] Figure 22. Provided technologies can increase levels of CXCL12 mRNA levels in vivo. From left to right: Agent 2423 (IV-15 mpk), Agent 2340 (IV-15 mpk), Agent 2418 (IV-15 mpk), Agent 2362 (IV-15 mpk), Agent 2572 (IV-15 mpk), Agent 2552 (IV-15 mpk), Agent 2668 (IV-15 mpk), Agent 2670 (IV-15 mpk), Agent 2317 (IV-15 mpk), Agent 2425 (IV-15 mpk), Agent 2410 (IV-15 mpk), Agent 2410 (SC-15 mpk), Agent 2410 (SC-30 mpk). Assessments were performed by qPCR in tumor samples taken from NU / J male mice with COLO320DM SC tumor model. Agents were delivered intravenously at a dosage of 15 mg / kg (IV-15 mpk), or subcutaneously at a dosage of 15 mg / kg (SC-15 mpk) or 30 mg / kg (SC-30 mpk). Single dose. Assessments were performed at 96 h after administration of agent. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9 for intravenous administration and 30 mM tris buffer pH 10.5-11 for subcutaneous administration. N=3 mice, all data shown as mean ± S.D.

[0072] Figure 23. Provided technologies can provide useful pharmacokinetic and pharmacodynamic profiles in vivo. From left to right: Agent 2317, Agent 2332, Agent 2337, Agent 2328, Agent 2348, Agent 2437, Agent 2722, Agent 2580, Agent 2577, Agent 1074, Agent 2818, Agent 2421, and Agent 2599. For each agent, provided data are levels of the agent (left, in µg / g), levels of beta-catenin polypeptide (center, in percent relative to vehicle), and levels of AXIN2 mRNA (right, in percent relative to vehicle). Assessments of Page 23 of 884 12834799v1Attorney Docket Number: 2012675-0389 beta-catenin polypeptide levels were performed by western blot of tumor samples. Assessments of AXIN2 mRNA levels were performed by qPCR in tumor samples. Agents were delivered intravenously at a dosage of 15 mg / kg. Single dose. Assessments were performed at 96 h after administration of agent. Tumor samples were taken from NU / J male mice with COLO320DM SC tumor model. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9. N=3 mice, all data shown as mean ± S.D.

[0073] Figure 24. Provided technologies can provide useful pharmacokinetic and pharmacodynamic profiles in vivo. From left to right: Agent 2624, Agent 2576, Agent 2558, Agent 2575, Agent 2312, Agent 2574, Agent 2406, Agent 2351, Agent 3147, Agent 2573, Agent 2336, Agent 2327, and Agent 2317. For each agent, provided data are levels of the agent (left, in µg / g), levels of beta-catenin polypeptide (center, in percent relative to vehicle), and levels of AXIN2 mRNA (right, in percent relative to vehicle). Assessments of beta-catenin polypeptide levels were performed by western blot of tumor samples. Assessments of AXIN2 mRNA levels were performed by qPCR in tumor samples. Agents were delivered intravenously at a dosage of 15 mg / kg. Single dose. Assessments were performed at 96 h after administration of agent. Tumor samples were taken from NU / J male mice with COLO320DM SC tumor model. Vehicle was 10% w / w DMSO in 30 mM tris, 5 mg / mL L-arginine, pH 8-9. N=3 mice, all data shown as mean ± S.D. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Definitions

[0074] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[0075] Administration: As used herein, the term “administration” typically refers to the administration of a composition to a subject or system. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e. g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a Page 24 of 884 12834799v1Attorney Docket Number: 2012675-0389 selected period of time.

[0076] Affinity: As is known in the art, “affinity” is a measure of the tightness with a particular ligand (e.g., an agent) binds to its partner (e.g., beta-catenin or a portion thereof). Affinities can be measured in different ways. In some embodiments, affinity is measured by a quantitative assay. In some such embodiments, binding partner concentration may be fixed to be in excess of ligand concentration so as to mimic physiological conditions. Alternatively or additionally, in some embodiments, binding partner concentration and / or ligand concentration may be varied. In some such embodiments, affinity may be compared to a reference under comparable conditions (e.g., concentrations).

[0077] Agent: In general, the term “agent”, as used herein, may be used to refer to a compound or entity of any chemical class including, for example, a polypeptide, nucleic acid, saccharide, lipid, small molecule, metal, or combination or complex thereof. In appropriate circumstances, as will be clear from context to those skilled in the art, the term may be utilized to refer to an entity that is or comprises a cell or organism, or a fraction, extract, or component thereof. Alternatively or additionally, as context will make clear, the term may be used to refer to a natural product in that it is found in and / or is obtained from nature. In some instances, again as will be clear from context, the term may be used to refer to one or more entities that is man-made in that it is designed, engineered, and / or produced through action of the hand of man and / or is not found in nature. In some embodiments, an agent may be utilized in isolated or pure form; in some embodiments, an agent may be utilized in crude form. In some embodiments, potential agents may be provided as collections or libraries, for example that may be screened to identify or characterize active agents within them. In some cases, the term “agent” may refer to a compound or entity that is or comprises a polymer; in some cases, the term may refer to a compound or entity that comprises one or more polymeric moieties. In some embodiments, the term “agent” may refer to a compound or entity that is not a polymer and / or is substantially free of any polymer and / or of one or more particular polymeric moieties. In some embodiments, the term may refer to a compound or entity that lacks or is substantially free of any polymeric moiety. In some embodiments, an agent is a compound. In some embodiments, an agent is a stapled peptide.

[0078] Aliphatic: As used herein, “aliphatic” means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a substituted or unsubstituted monocyclic, bicyclic, or polycyclic hydrocarbon ring that is completely saturated or that contains one or more units of unsaturation (but not aromatic), or combinations thereof. In some embodiments, aliphatic groups contain 1-50 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-20 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-9 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-7 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1, 2, 3, or 4 aliphatic carbon atoms. Suitable aliphatic groups include, Page 25 of 884 12834799v1Attorney Docket Number: 2012675-0389 but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0079] Alkenyl: As used herein, the term “alkenyl” refers to an aliphatic group, as defined herein, having one or more double bonds.

[0080] Alkyl: As used herein, the term “alkyl” is given its ordinary meaning in the art and may include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In some embodiments, alkyl has 1-50 carbon atoms. In certain embodiments, a straight chain or branched chain alkyl has about 1-20 carbon atoms in its backbone (e.g., C1-C20for straight chain, C2-C20for branched chain), and alternatively, about 1-10. In some embodiments, cycloalkyl rings have from about 3-10 carbon atoms in their ring structure where such rings are monocyclic, bicyclic, or polycyclic, and alternatively about 5, 6 or 7 carbons in the ring structure. In some embodiments, an alkyl group may be a lower alkyl group, wherein a lower alkyl group comprises 1-4 carbon atoms (e.g., C1-C4for straight chain lower alkyls).

[0081] Amino acid: In its broadest sense, as used herein, refers to any compound and / or substance that can be incorporated into a polypeptide chain, e.g., through formation of one or more peptide bonds. In some embodiments, an amino acid comprising an amino group and an a carboxylic acid group. In some embodiments, an amino acid has the structure of NH(Ra1)−La1−C(Ra2)(Ra3)−La2−COOH, wherein each variable is independently as described in the present disclosure. In some embodiments, an amino acid has the general structure NH(R’)–C(R’)2–COOH, wherein each R’ is independently as described in the present disclosure. In some embodiments, an amino acid has the general structure H2N–C(R’)2–COOH, wherein R’ is as described in the present disclosure. In some embodiments, an amino acid has the general structure H2N– C(H)(R’)–COOH, wherein R’ is as described in the present disclosure. In some embodiments, an amino acid is a naturally-occurring amino acid. In some embodiments, an amino acid is a non-natural amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid. “Standard amino acid” refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. “Nonstandard amino acid” refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source. In some embodiments, an amino acid, including a carboxy- and / or amino-terminal amino acid in a polypeptide, can contain a structural modification as compared with the general structure above. For example, in some embodiments, an amino acid may be modified by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and / or substitution (e.g., of the amino group, the carboxylic acid group, one or more protons, one or more hydrogens, and / or the hydroxyl group) as compared with the general structure. In some embodiments, such modification may, for example, alter the circulating half-life of a polypeptide containing the modified amino acid as compared with one containing an otherwise identical unmodified amino acid. In some embodiments, such modification does not significantly alter a relevant activity of a polypeptide containing the modified amino acid, as compared with one containing an otherwise identical unmodified amino acid. As will be clear Page 26 of 884 12834799v1Attorney Docket Number: 2012675-0389 from context, in some embodiments, the term “amino acid” may be used to refer to a free amino acid; in some embodiments it may be used to refer to an amino acid residue of a polypeptide.

[0082] Analog: As used herein, the term “analog” refers to a substance that shares one or more particular structural features, elements, components, or moieties with a reference substance. Typically, an “analog” shows significant structural similarity with the reference substance, for example sharing a core or consensus structure, but also differs in certain discrete ways. In some embodiments, an analog is a substance that can be generated from the reference substance, e.g., by chemical manipulation of the reference substance. In some embodiments, an analog is a substance that can be generated through performance of a synthetic process substantially similar to (e.g., sharing a plurality of steps with) one that generates the reference substance. In some embodiments, an analog is or can be generated through performance of a synthetic process different from that used to generate the reference substance.

[0083] Animal: As used herein refers to any member of the animal kingdom. In some embodiments, "animal" refers to humans, of either sex and at any stage of development. In some embodiments, "animal" refers to non-human animals, at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and / or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or worms. In some embodiments, an animal may be a transgenic animal, genetically engineered animal, and / or a clone.

[0084] Approximately: As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0085] Aryl: The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” “aryloxyalkyl,” etc. refers to monocyclic, bicyclic or polycyclic ring systems having a total of five to thirty ring members, wherein at least one ring in the system is aromatic. In some embodiments, an aryl group is a monocyclic, bicyclic or polycyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. In some embodiments, an aryl group is a biaryl group. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthracyl and the like, which may bear one or more substituents. In some embodiments, also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like, where a radical or point of attachment is on an aryl ring. Page 27 of 884 12834799v1Attorney Docket Number: 2012675-0389

[0086] Associated with: Two events or entities are “associated” with one another, as that term is used herein, if the presence, level and / or form of one is correlated with that of the other. For example, a particular entity (e.g., nucleic acid (e.g., genomic DNA, transcripts, mRNA, etc.), polypeptide, genetic signature, metabolite, microbe, etc..) is considered to be associated with a particular disease, disorder, or condition, if its presence, level and / or form correlates with incidence of and / or susceptibility to the disease, disorder, or condition (e.g., across a relevant population).

[0087] Binding: It will be understood that the term “binding”, as used herein, typically refers to a non- covalent association between or among agents. In many embodiments herein, binding is addressed with respect to particular agents and beta-catenin. It will be appreciated by those of ordinary skill in the art that such binding may be assessed in any of a variety of contexts. In some embodiments, binding is assessed with respect to beta-catenin. In some embodiments, binding is assessed with respect to one or more amino acid residues of beta-catenin. In some embodiments, binding is assessed with respect to one or more amino acid residues corresponding to (e.g., similarly positioned in three dimensional space and / or having certain similar properties and / or functions) those of beta-catenin.

[0088] Binding site: The term “binding site”, as used herein, refers to a region of a target polypeptide, formed in three-dimensional space, that includes one or more or all interaction residues of the target polypeptide. In some embodiments, “binding site” may refer to one or more amino acid residues which comprise or are one or more or all interaction amino acid residues of a target polypeptide. As will be understood by those of ordinary skill in the art, a binding site may include residues that are adjacent to one another on a linear chain, and / or that are distal to one another on a linear chain but near to one another in three-dimensional space when a target polypeptide is folded. A binding site may comprise amino acid residues and / or saccharide residues.

[0089] Carrier: as used herein, refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, carriers are or include one or more solid components.

[0090] Comparable: As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison there between so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed. In some embodiments, comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable. For example, those of ordinary skill in the art will appreciate that sets of circumstances, individuals, or populations are comparable Page 28 of 884 12834799v1Attorney Docket Number: 2012675-0389 to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied.

[0091] Composition: Those skilled in the art will appreciate that the term “composition” may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form – e.g., gas, gel, liquid, solid, etc.

[0092] Cycloaliphatic: The term “cycloaliphatic,” as used herein, refers to saturated or partially unsaturated aliphatic monocyclic, bicyclic, or polycyclic ring systems having, e.g., from 3 to 30, members, wherein the aliphatic ring system is optionally substituted. Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, the cycloalkyl has 3–6 carbons. The terms “cycloaliphatic” may also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, where a radical or point of attachment is on an aliphatic ring. In some embodiments, a carbocyclic group is bicyclic. In some embodiments, a carbocyclic group is tricyclic. In some embodiments, a carbocyclic group is polycyclic. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C10, or C3- C6hydrocarbon, or a C4-C10, or C8-C10bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, or a C9-C16tricyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic.

[0093] Derivative: As used herein, the term “derivative” refers to a structural analogue of a reference substance. That is, a “derivative” is a substance that shows significant structural similarity with the reference substance, for example sharing a core or consensus structure, but also differs in certain discrete ways. In some embodiments, a derivative is a substance that can be generated from the reference substance by chemical manipulation. In some embodiments, a derivative is a substance that can be generated through performance of a synthetic process substantially similar to (e.g., sharing a plurality of steps with) one that generates the reference substance.

[0094] Dosage form or unit dosage form: Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen). Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms. Page 29 of 884 12834799v1Attorney Docket Number: 2012675-0389

[0095] Dosing regimen: Those skilled in the art will appreciate that the term “dosing regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0096] Engineered: In general, the term “engineered” refers to the aspect of having been manipulated by the hand of man. For example, in some embodiments, a peptide may be considered to be engineered if its amino acid sequence has been selected by man. For example, an engineered agent has an amino acid sequence that was selected based on preferences for corresponding amino acids at particular sites of protein- protein interactions. In some embodiments, an engineered sequence has an amino acid sequence that differs from the amino acid sequence of polypeptides included in the NCBI database that binds to a TCF site of beta- catenin. In many embodiments, provided agents are engineered agents. In some embodiments, engineered agents are peptide agents comprising non-natural amino acid residues, non-natural amino acid sequences, and / or peptide staples. In some embodiments, provided agents comprise or are engineered peptide agents which comprise engineered sequences.

[0097] Halogen: The term “halogen” means F, Cl, Br, or I.

[0098] Heteroaliphatic: The term “heteroaliphatic” is given its ordinary meaning in the art and refers to aliphatic groups as described herein in which one or more carbon atoms are replaced with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, and the like).

[0099] Heteroalkyl: The term “heteroalkyl” is given its ordinary meaning in the art and refers to alkyl groups as described herein in which one or more carbon atoms is replaced with a heteroatom (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, and the like). Examples of heteroalkyl groups include, but are not limited to, alkoxy, poly(ethylene glycol)-, alkyl-substituted amino, tetrahydrofuranyl, piperidinyl, morpholinyl, etc.

[0100] Heteroaryl: The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to monocyclic, bicyclic or polycyclic ring systems having, for example, a total of five to thirty, e.g., 5, 6, 9, 10, 14, etc., ring members, wherein at least one ring in the Page 30 of 884 12834799v1Attorney Docket Number: 2012675-0389 system is aromatic and at least one aromatic ring atom is a heteroatom. In some embodiments, a heteroatom is nitrogen, oxygen or sulfur. In some embodiments, a heteroaryl group is a group having 5 to 10 ring atoms (i.e., monocyclic, bicyclic or polycyclic), in some embodiments 5, 6, 9, or 10 ring atoms. In some embodiments, a heteroaryl group has 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. In some embodiments, a heteroaryl is a heterobiaryl group, such as bipyridyl and the like. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where a radical or point of attachment is on a heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one. A heteroaryl group may be monocyclic, bicyclic or polycyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl group, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0101] Heteroatom: The term “heteroatom” means an atom that is not carbon and is not hydrogen. In some embodiments, a heteroatom is oxygen, sulfur, nitrogen, phosphorus, boron or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or a substitutable nitrogen of a heterocyclic ring (for example, N as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl); etc.). In some embodiments, a heteroatom is boron, nitrogen, oxygen, silicon, sulfur, or phosphorus. In some embodiments, a heteroatom is nitrogen, oxygen, silicon, sulfur, or phosphorus. In some embodiments, a heteroatom is nitrogen, oxygen, sulfur, or phosphorus. In some embodiments, a heteroatom is nitrogen, oxygen or sulfur.

[0102] Heterocyclyl: As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a monocyclic, bicyclic or polycyclic ring moiety (e.g., 3-30 membered) that is saturated or partially unsaturated and has one or more heteroatom ring atoms. In some embodiments, a heteroatom is boron, nitrogen, oxygen, silicon, sulfur, or phosphorus. In some embodiments, a heteroatom is nitrogen, oxygen, silicon, sulfur, or phosphorus. In some embodiments, a heteroatom is nitrogen, oxygen, sulfur, or phosphorus. In some embodiments, a heteroatom is nitrogen, oxygen or sulfur. In some embodiments, a heterocyclyl group is a stable 5– to 7–membered monocyclic or 7– to 10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in Page 31 of 884 12834799v1Attorney Docket Number: 2012675-0389 a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where a radical or point of attachment is on a heteroaliphatic ring. A heterocyclyl group may be monocyclic, bicyclic or polycyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0103] Homology: As used herein, the term “homology” refers to the overall relatedness between polymeric molecules, e.g., between nucleic acid molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. In some embodiments, polymeric molecules are considered to be “homologous” to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical. In some embodiments, polymeric molecules are considered to be “homologous” to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% similar (e.g., containing residues with related chemical properties at corresponding positions). For example, as is well known by those of ordinary skill in the art, certain amino acids are typically classified as similar to one another as “hydrophobic” or “hydrophilic” amino acids, and / or as having “polar” or “non-polar” side chains. Substitution of one amino acid for another of the same type may often be considered a “homologous” substitution. Typical amino acid categorizations are summarized below (hydrophobicity scale of Kyte and Doolittle, 1982: A simple method for displaying the hydropathic character of a protein. J. Mol. Biol.157:105-132): Amino Acid3 Letter1 Letter Side Chain Side Chain Hydropathy Index of CdC d P l i A idi / B i i K d D li le12834799v1Attorney Docket Number: 2012675-0389 Leucine Leu L nonpolar neutral 3.8 Lysine Lys K polar basic -3.9 hi i l lAsparagine or aspartic acid Asx B [0104, t permit comparison of sequences in order to determine their degree of homology, including by permitting gaps of designated length in one sequence relative to another when considering which residues “correspond” to one another in different sequences. Calculation of the percent homology between two nucleic acid sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and non- corresponding sequences can be disregarded for comparison purposes). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or substantially 100% of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position; when a position in the first sequence is occupied by a similar nucleotide as the corresponding position in the second sequence, then the molecules are similar at that position. The percent homology between the two sequences is a function of the number of identical and similar positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. Representative algorithms and computer programs useful in determining the percent homology between two nucleotide sequences include, for example, the algorithm of Meyers and Miller (CABIOS, 1989, 4: 11-17), which has been incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent homology between two nucleotide sequences can, alternatively, be determined for example using the GAP program in the GCG software package using an NWSgapdna.CMP matrix.

[0105] Interaction residues: The term “interaction residues”, “interaction motifs”, as used herein, refers to, with respect to an agent, residues or motifs in an agent that are designed to interact with particular target Page 33 of 884 12834799v1Attorney Docket Number: 2012675-0389 residues in a target polypeptide, or with respect to a target polypeptide, residues in a target polypeptide that interact with particular motifs (e.g., aromatic groups, amino acid residues, etc.) of an agent. Specifically, interaction residues and motifs of various agents are selected and arranged within the agents so that they will be displayed in three dimensional space within a predetermined distance (or volume) of identified target residues (e.g., upon binding, docking or other interaction assays). In many embodiments, interaction residues are direct-binding residues.

[0106] Improved, increased, decreased, or reduced: As used herein, these terms, or grammatically comparable comparative terms, indicate values that are relative to a comparable reference measurement. For example, in some embodiments, an assessed value achieved with an agent of interest may be “improved” relative to that obtained with a comparable reference agent. Alternatively or additionally, in some embodiments, an assessed value achieved in a subject or system of interest may be “improved” relative to that obtained in the same subject or system under different conditions (e.g., prior to or after an event such as administration of an agent of interest), or in a different, comparable subject (e.g., in a comparable subject or system that differs from the subject or system of interest in presence of one or more indicators of a particular disease, disorder or condition of interest, or in prior exposure to a condition or agent, etc). In some embodiments, comparative terms refer to statistically relevant differences (e.g., that are of a prevalence and / or magnitude sufficient to achieve statistical relevance). Those skilled in the art will be aware, or will readily be able to determine, in a given context, a degree and / or prevalence of difference that is required or sufficient to achieve such statistical significance.

[0107] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass groups having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties.

[0108] Peptide: The term “peptide” as used herein refers to a polypeptide. In some embodiments, a peptide is a polypeptide that is relatively short, for example having a length of less than about 100 amino acids, less than about 50 amino acids, less than about 40 amino acids less than about 30 amino acids, less than about 25 amino acids, less than about 20 amino acids, less than about 15 amino acids, or less than 10 amino acids. In some embodiments, a length is about 5-20, 5-19, 5-18, 5-17, 5-16, 5-15, 10-20, 10-19, 10-18, 10-17, 10-16, 10-15, 11-20, 11-19, 11-18, 11-17, 11-16, 11-15, 12-20, 12-19, 12-18, 12-17, 12-16, 12-15, 13-20, 13- 19, 13-18, 13-17, 13-16, 13-15, 14-20, 14-19, 14-18, 14-17, 14-16, 14-15, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids.

[0109] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral Page 34 of 884 12834799v1Attorney Docket Number: 2012675-0389 administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0110] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0111] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; RingeR’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0112] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, Page 35 of 884 12834799v1Attorney Docket Number: 2012675-0389 tartaric acid, citric acid, succinic acid or malonic acid or by using other known methods such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic base addition salts, such as those formed by acidic groups of provided compounds with bases. Representative alkali or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, pharmaceutically acceptable salts are ammonium salts (e.g., −N(R)3+). In some embodiments, pharmaceutically acceptable salts are sodium salts. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

[0113] Polypeptide: As used herein refers to any polymeric chain of amino acids. In some embodiments, a polypeptide has an amino acid sequence that occurs in nature. In some embodiments, a polypeptide has an amino acid sequence that does not occur in nature. In some embodiments, a polypeptide has an amino acid sequence that is engineered in that it is designed and / or produced through action of the hand of man. In some embodiments, a polypeptide may comprise or consist of natural amino acids, non-natural amino acids, or both. In some embodiments, a polypeptide may comprise or consist of only natural amino acids or only non- natural amino acids. In some embodiments, a polypeptide may comprise D-amino acids, L-amino acids, or both. In some embodiments, a polypeptide may comprise only D-amino acids. In some embodiments, a polypeptide may comprise only L-amino acids. In some embodiments, a polypeptide may include one or more pendant groups or other modifications, e.g., modifying or attached to one or more amino acid side chains, at the polypeptide’s N-terminus, at the polypeptide’s C-terminus, or any combination thereof. In some embodiments, such pendant groups or modifications may be selected from the group consisting of acetylation, amidation, lipidation, methylation, pegylation, etc., including combinations thereof. In some embodiments, a polypeptide may be cyclic, and / or may comprise a cyclic portion. In some embodiments, a polypeptide is not cyclic and / or does not comprise any cyclic portion. In some embodiments, a polypeptide is linear. In some embodiments, a polypeptide may be or comprise a stapled polypeptide. In some embodiments, the term “polypeptide” may be appended to a name of a reference polypeptide, activity, or structure; in such instances it is used herein to refer to polypeptides that share the relevant activity or structure and thus can be considered to be members of the same class or family of polypeptides. For each such class, the present Page 36 of 884 12834799v1Attorney Docket Number: 2012675-0389 specification provides and / or those skilled in the art will be aware of exemplary polypeptides within the class whose amino acid sequences and / or functions are known; in some embodiments, such exemplary polypeptides are reference polypeptides for the polypeptide class or family. In some embodiments, a member of a polypeptide class or family shows significant sequence homology or identity with, shares a common sequence motif (e.g., a characteristic sequence element) with, and / or shares a common activity (in some embodiments at a comparable level or within a designated range) with a reference polypeptide of the class; in some embodiments with all polypeptides within the class). For example, in some embodiments, a member polypeptide shows an overall degree of sequence homology or identity with a reference polypeptide that is at least about 30-40%, and is often greater than about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more and / or includes at least one region (e.g., a conserved region that may in some embodiments be or comprise a characteristic sequence element) that shows very high sequence identity, often greater than 90% or even 95%, 96%, 97%, 98%, or 99%. Such a conserved region usually encompasses at least 3-4 and often up to 20 or more amino acids; in some embodiments, a conserved region encompasses at least one stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more contiguous amino acids. In some embodiments, a relevant polypeptide may comprise or consist of a fragment of a parent polypeptide. In some embodiments, a useful polypeptide as may comprise or consist of a plurality of fragments, each of which is found in the same parent polypeptide in a different spatial arrangement relative to one another than is found in the polypeptide of interest (e.g., fragments that are directly linked in the parent may be spatially separated in the polypeptide of interest or vice versa, and / or fragments may be present in a different order in the polypeptide of interest than in the parent), so that the polypeptide of interest is a derivative of its parent polypeptide.

[0114] Prevent or prevention: as used herein when used in connection with the occurrence of a disease, disorder, and / or condition, refers to reducing the risk of developing the disease, disorder and / or condition and / or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

[0115] Protecting group: The term “protecting group,” as used herein, is well known in the art and includes those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Also included are those protecting groups specially adapted for nucleoside and nucleotide chemistry described in Current Protocols in Nucleic Acid Chemistry, edited by Serge L. Beaucage et al.06 / 2012, the entirety of Chapter 2 is incorporated herein by reference. Suitable amino–protecting groups include methyl carbamate, ethyl carbamante, 9–fluorenylmethyl carbamate (Fmoc), 9–(2–sulfo)fluorenylmethyl carbamate, 9–(2,7– dibromo)fluoroenylmethyl carbamate, 2,7–di–t–butyl–[9–(10,10–dioxo–10,10,10,10– tetrahydrothioxanthyl)]methyl carbamate (DBD–Tmoc), 4–methoxyphenacyl carbamate (Phenoc), 2,2,2– trichloroethyl carbamate (Troc), 2–trimethylsilylethyl carbamate (Teoc), 2–phenylethyl carbamate (hZ), 1– Page 37 of 884 12834799v1Attorney Docket Number: 2012675-0389 (1–adamantyl)–1–methylethyl carbamate (Adpoc), 1,1–dimethyl–2–haloethyl carbamate, 1,1–dimethyl–2,2– dibromoethyl carbamate (DB–t–BOC), 1,1–dimethyl–2,2,2–trichloroethyl carbamate (TCBOC), 1–methyl–1– (4–biphenylyl)ethyl carbamate (Bpoc), 1–(3,5–di–t–butylphenyl)–1–methylethyl carbamate (t–Bumeoc), 2– (2’– and 4’–pyridyl)ethyl carbamate (Pyoc), 2–(N,N–dicyclohexylcarboxamido)ethyl carbamate, t–butyl carbamate (BOC), 1–adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1– isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4–nitrocinnamyl carbamate (Noc), 8–quinolyl carbamate, N–hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p– methoxybenzyl carbamate (Moz), p–nitobenzyl carbamate, p–bromobenzyl carbamate, p–chlorobenzyl carbamate, 2,4–dichlorobenzyl carbamate, 4–methylsulfinylbenzyl carbamate (Msz), 9–anthrylmethyl carbamate, diphenylmethyl carbamate, 2–methylthioethyl carbamate, 2–methylsulfonylethyl carbamate, 2– (p–toluenesulfonyl)ethyl carbamate, [2–(1,3–dithianyl)]methyl carbamate (Dmoc), 4–methylthiophenyl carbamate (Mtpc), 2,4–dimethylthiophenyl carbamate (Bmpc), 2–phosphonioethyl carbamate (Peoc), 2– triphenylphosphonioisopropyl carbamate (Ppoc), 1,1–dimethyl–2–cyanoethyl carbamate, m–chloro–p– acyloxybenzyl carbamate, p–(dihydroxyboryl)benzyl carbamate, 5–benzisoxazolylmethyl carbamate, 2– (trifluoromethyl)–6–chromonylmethyl carbamate (Tcroc), m–nitrophenyl carbamate, 3,5–dimethoxybenzyl carbamate, o–nitrobenzyl carbamate, 3,4–dimethoxy–6–nitrobenzyl carbamate, phenyl(o–nitrophenyl)methyl carbamate, phenothiazinyl–(10)–carbonyl derivative, N’–p–toluenesulfonylaminocarbonyl derivative, N’– phenylaminothiocarbonyl derivative, t–amyl carbamate, S–benzyl thiocarbamate, p–cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p– decyloxybenzyl carbamate, 2,2–dimethoxycarbonylvinyl carbamate, o–(N,N–dimethylcarboxamido)benzyl carbamate, 1,1–dimethyl–3–(N,N–dimethylcarboxamido)propyl carbamate, 1,1–dimethylpropynyl carbamate, di(2–pyridyl)methyl carbamate, 2–furanylmethyl carbamate, 2–iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p–(p’–methoxyphenylazo)benzyl carbamate, 1– methylcyclobutyl carbamate, 1–methylcyclohexyl carbamate, 1–methyl–1–cyclopropylmethyl carbamate, 1– methyl–1–(3,5–dimethoxyphenyl)ethyl carbamate, 1–methyl–1–(p–phenylazophenyl)ethyl carbamate, 1– methyl–1–phenylethyl carbamate, 1–methyl–1–(4–pyridyl)ethyl carbamate, phenyl carbamate, p– (phenylazo)benzyl carbamate, 2,4,6–tri–t–butylphenyl carbamate, 4–(trimethylammonium)benzyl carbamate, 2,4,6–trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3–phenylpropanamide, picolinamide, 3–pyridylcarboxamide, N– benzoylphenylalanyl derivative, benzamide, p–phenylbenzamide, o–nitophenylacetamide, o– nitrophenoxyacetamide, acetoacetamide, (N’–dithiobenzyloxycarbonylamino)acetamide, 3–(p– hydroxyphenyl)propanamide, 3–(o–nitrophenyl)propanamide, 2–methyl–2–(o–nitrophenoxy)propanamide, 2–methyl–2–(o–phenylazophenoxy)propanamide, 4–chlorobutanamide, 3–methyl–3–nitrobutanamide, o– nitrocinnamide, N–acetylmethionine derivative, o–nitrobenzamide, o–(benzoyloxymethyl)benzamide, 4,5– diphenyl–3–oxazolin–2–one, N–phthalimide, N–dithiasuccinimide (Dts), N–2,3–diphenylmaleimide, N–2,5– dimethylpyrrole, N–1,1,4,4–tetramethyldisilylazacyclopentane adduct (STABASE), 5–substituted 1,3– Page 38 of 884 12834799v1Attorney Docket Number: 2012675-0389 dimethyl–1,3,5–triazacyclohexan–2–one, 5–substituted 1,3–dibenzyl–1,3,5–triazacyclohexan–2–one, 1– substituted 3,5–dinitro–4–pyridone, N–methylamine, N–allylamine, N–[2– (trimethylsilyl)ethoxy]methylamine (SEM), N–3–acetoxypropylamine, N–(1–isopropyl–4–nitro–2–oxo–3– pyroolin–3–yl)amine, quaternary ammonium salts, N–benzylamine, N–di(4–methoxyphenyl)methylamine, N–5–dibenzosuberylamine, N–triphenylmethylamine (Tr), N–[(4–methoxyphenyl)diphenylmethyl]amine (MMTr), N–9–phenylfluorenylamine (PhF), N–2,7–dichloro–9–fluorenylmethyleneamine, N– ferrocenylmethylamino (Fcm), N–2–picolylamino N’–oxide, N–1,1–dimethylthiomethyleneamine, N– benzylideneamine, N–p–methoxybenzylideneamine, N–diphenylmethyleneamine, N–[(2– pyridyl)mesityl]methyleneamine, N–(N’,N’–dimethylaminomethylene)amine, N,N’–isopropylidenediamine, N–p–nitrobenzylideneamine, N–salicylideneamine, N–5–chlorosalicylideneamine, N–(5–chloro–2– hydroxyphenyl)phenylmethyleneamine, N–cyclohexylideneamine, N–(5,5–dimethyl–3–oxo–1– cyclohexenyl)amine, N–borane derivative, N–diphenylborinic acid derivative, N– [phenyl(pentacarbonylchromium– or tungsten)carbonyl]amine, N–copper chelate, N–zinc chelate, N– nitroamine, N–nitrosoamine, amine N–oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o–nitrobenzenesulfenamide (Nps), 2,4–dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2–nitro–4–methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3– nitropyridinesulfenamide (Npys), p–toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,–trimethyl–4– methoxybenzenesulfonamide (Mtr), 2,4,6–trimethoxybenzenesulfonamide (Mtb), 2,6–dimethyl–4– methoxybenzenesulfonamide (Pme), 2,3,5,6–tetramethyl–4–methoxybenzenesulfonamide (Mte), 4– methoxybenzenesulfonamide (Mbs), 2,4,6–trimethylbenzenesulfonamide (Mts), 2,6–dimethoxy–4– methylbenzenesulfonamide (iMds), 2,2,5,7,8–pentamethylchroman–6–sulfonamide (Pmc), methanesulfonamide (Ms), β–trimethylsilylethanesulfonamide (SES), 9–anthracenesulfonamide, 4–(4’,8’– dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0116] In some embodiments, suitable mono-protected amines include, but are not limited to, aralkylamines, carbamates, allyl amines, amides, and the like. Examples of suitable mono-protected amino moieties include t-butyloxycarbonylamino (–NHBOC), ethyloxycarbonylamino, methyloxycarbonylamino, trichloroethyloxycarbonylamino, allyloxycarbonylamino (–NHAlloc), benzyloxocarbonylamino (–NHCBZ), allylamino, benzylamino (–NHBn), fluorenylmethylcarbonyl (–NHFmoc), formamido, acetamido, chloroacetamido, dichloroacetamido, trichloroacetamido, phenylacetamido, trifluoroacetamido, benzamido, t- butyldiphenylsilyl, and the like. In some embodiments, suitable di-protected amines include amines that are substituted with two substituents independently selected from those described above as mono-protected amines, and further include cyclic imides, such as phthalimide, maleimide, succinimide, and the like. In some embodiments, suitable di-protected amines include pyrroles and the like, 2,2,5,5-tetramethyl- [1,2,5]azadisilolidine and the like, and azide. Page 39 of 884 12834799v1Attorney Docket Number: 2012675-0389

[0117] Suitably protected carboxylic acids further include, but are not limited to, silyl–, alkyl–, alkenyl–, aryl–, and arylalkyl–protected carboxylic acids. Examples of suitable silyl groups include trimethylsilyl, triethylsilyl, t–butyldimethylsilyl, t–butyldiphenylsilyl, triisopropylsilyl, and the like. Examples of suitable alkyl groups include methyl, benzyl, p–methoxybenzyl, 3,4–dimethoxybenzyl, trityl, t–butyl, tetrahydropyran–2–yl. Examples of suitable alkenyl groups include allyl. Examples of suitable aryl groups include optionally substituted phenyl, biphenyl, or naphthyl. Examples of suitable arylalkyl groups include optionally substituted benzyl (e.g., p–methoxybenzyl (MPM), 3,4–dimethoxybenzyl, O–nitrobenzyl, p– nitrobenzyl, p–halobenzyl, 2,6–dichlorobenzyl, p–cyanobenzyl), and 2– and 4–picolyl. In some embodiments, suitable protected carboxylic acids include, but are not limited to, optionally substituted C1–6aliphatic esters, optionally substituted aryl esters, silyl esters, activated esters, amides, hydrazides, and the like. Examples of such ester groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, and phenyl ester, wherein each group is optionally substituted. Additional suitable protected carboxylic acids include oxazolines and ortho esters.

[0118] Suitable hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t–butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p– methoxybenzyloxymethyl (PMBM), (4–methoxyphenoxy)methyl (p–AOM), guaiacolmethyl (GUM), t– butoxymethyl, 4–pentenyloxymethyl (POM), siloxymethyl, 2–methoxyethoxymethyl (MEM), 2,2,2– trichloroethoxymethyl, bis(2–chloroethoxy)methyl, 2–(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3–bromotetrahydropyranyl, tetrahydrothiopyranyl, 1–methoxycyclohexyl, 4– methoxytetrahydropyranyl (MTHP), 4–methoxytetrahydrothiopyranyl, 4–methoxytetrahydrothiopyranyl S,S– dioxide, 1–[(2–chloro–4–methyl)phenyl]–4–methoxypiperidin–4–yl (CTMP), 1,4–dioxan–2–yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a–octahydro–7,8,8–trimethyl–4,7– methanobenzofuran–2–yl, 1–ethoxyethyl, 1–(2–chloroethoxy)ethyl, 1–methyl–1–methoxyethyl, 1–methyl–1– benzyloxyethyl, 1–methyl–1–benzyloxy–2–fluoroethyl, 2,2,2–trichloroethyl, 2–trimethylsilylethyl, 2– (phenylselenyl)ethyl, t–butyl, allyl, p–chlorophenyl, p–methoxyphenyl, 2,4–dinitrophenyl, benzyl, p– methoxybenzyl, 3,4–dimethoxybenzyl, o–nitrobenzyl, p–nitrobenzyl, p–halobenzyl, 2,6–dichlorobenzyl, p– cyanobenzyl, p–phenylbenzyl, 2–picolyl, 4–picolyl, 3–methyl–2–picolyl N–oxido, diphenylmethyl, p,p’– dinitrobenzhydryl, 5–dibenzosuberyl, triphenylmethyl, α–naphthyldiphenylmethyl, p– methoxyphenyldiphenylmethyl, di(p–methoxyphenyl)phenylmethyl, tri(p–methoxyphenyl)methyl, 4–(4’– bromophenacyloxyphenyl)diphenylmethyl, 4,4’,4’’–tris(4,5–dichlorophthalimidophenyl)methyl, 4,4’,4’’– tris(levulinoyloxyphenyl)methyl, 4,4’,4’’–tris(benzoyloxyphenyl)methyl, 3–(imidazol–1–yl)bis(4’,4’’– dimethoxyphenyl)methyl, 1,1–bis(4–methoxyphenyl)–1’–pyrenylmethyl, 9–anthryl, 9–(9–phenyl)xanthenyl, 9–(9–phenyl–10–oxo)anthryl, 1,3–benzodithiolan–2–yl, benzisothiazolyl S,S–dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t–butyldimethylsilyl (TBDMS), t–butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri–p– xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t–butylmethoxyphenylsilyl (TBMPS), formate, Page 40 of 884 12834799v1Attorney Docket Number: 2012675-0389 benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p–chlorophenoxyacetate, 3–phenylpropionate, 4–oxopentanoate (levulinate), 4,4–(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4– methoxycrotonate, benzoate, p–phenylbenzoate, 2,4,6–trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9–fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2–trichloroethyl carbonate (Troc), 2– (trimethylsilyl)ethyl carbonate (TMSEC), 2–(phenylsulfonyl) ethyl carbonate (Psec), 2– (triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p–nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p–methoxybenzyl carbonate, alkyl 3,4–dimethoxybenzyl carbonate, alkyl o–nitrobenzyl carbonate, alkyl p–nitrobenzyl carbonate, alkyl S– benzyl thiocarbonate, 4–ethoxy–1–napththyl carbonate, methyl dithiocarbonate, 2–iodobenzoate, 4– azidobutyrate, 4–nitro–4–methylpentanoate, o–(dibromomethyl)benzoate, 2–formylbenzenesulfonate, 2– (methylthiomethoxy)ethyl, 4–(methylthiomethoxy)butyrate, 2–(methylthiomethoxymethyl)benzoate, 2,6– dichloro–4–methylphenoxyacetate, 2,6–dichloro–4–(1,1,3,3–tetramethylbutyl)phenoxyacetate, 2,4–bis(1,1– dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)–2–methyl–2– butenoate, o–(methoxycarbonyl)benzoate, α–naphthoate, nitrate, alkyl N,N,N’,N’– tetramethylphosphorodiamidate, alkyl N–phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4– dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). For protecting 1,2– or 1,3–diols, the protecting groups include methylene acetal, ethylidene acetal, 1–t– butylethylidene ketal, 1–phenylethylidene ketal, (4–methoxyphenyl)ethylidene acetal, 2,2,2– trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p–methoxybenzylidene acetal, 2,4–dimethoxybenzylidene ketal, 3,4– dimethoxybenzylidene acetal, 2–nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1–methoxyethylidene ortho ester, 1–ethoxyethylidine ortho ester, 1,2– dimethoxyethylidene ortho ester, α–methoxybenzylidene ortho ester, 1–(N,N–dimethylamino)ethylidene derivative, α–(N,N’–dimethylamino)benzylidene derivative, 2–oxacyclopentylidene ortho ester, di–t– butylsilylene group (DTBS), 1,3–(1,1,3,3–tetraisopropyldisiloxanylidene) derivative (TIPDS), tetra–t– butoxydisiloxane–1,3–diylidene derivative (TBDS), cyclic carbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

[0119] In some embodiments, a hydroxyl protecting group is acetyl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1 -ethoxyethyl, 1 -(2-chloroethoxy)ethyl, 2- trimethylsilylethyl, p- chlorophenyl, 2,4-dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6- dichlorobenzyl, diphenylmethyl, p- nitrobenzyl, triphenylmethyl (trityl), 4,4'-dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t- butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifiuoroacetyl, pivaloyl, 9- fluorenylmethyl carbonate, mesylate, tosylate, triflate, trityl, monomethoxytrityl (MMTr), 4,4'-dimethoxytrityl, (DMTr) and 4,4',4''-trimethoxytrityl (TMTr), 2-cyanoethyl (CE or Cne), 2- (trimethylsilyl)ethyl (TSE), 2-(2-nitrophenyl)ethyl, 2-(4-cyanophenyl)ethyl 2-(4-nitrophenyl)ethyl (NPE), 2- Page 41 of 884 12834799v1Attorney Docket Number: 2012675-0389 (4-nitrophenylsulfonyl)ethyl, 3,5-dichlorophenyl, 2,4-dimethylphenyl, 2-nitrophenyl, 4-nitrophenyl, 2,4,6- trimethylphenyl, 2-(2-nitrophenyl)ethyl, butylthiocarbonyl, 4,4',4''-tris(benzoyloxy)trityl, diphenylcarbamoyl, levulinyl, 2-(dibromomethyl)benzoyl (Dbmb), 2-(isopropylthiomethoxymethyl)benzoyl (Ptmt), 9- phenylxanthen-9-yl (pixyl) or 9-(p-methoxyphenyl)xanthine-9-y1 (MOX). In some embodiments, each of the hydroxyl protecting groups is, independently selected from acetyl, benzyl, t- butyldimethylsilyl, t- butyldiphenylsilyl and 4,4'-dimethoxytrityl. In some embodiments, the hydroxyl protecting group is selected from the group consisting of trityl, monomethoxytrityl and 4,4'-dimethoxytrityl group. In some embodiments, a phosphorous linkage protecting group is a group attached to the phosphorous linkage (e.g., an internucleotidic linkage) throughout oligonucleotide synthesis. In some embodiments, a protecting group is attached to a sulfur atom of an phosphorothioate group. In some embodiments, a protecting group is attached to an oxygen atom of an internucleotide phosphorothioate linkage. In some embodiments, a protecting group is attached to an oxygen atom of the internucleotide phosphate linkage. In some embodiments a protecting group is 2-cyanoethyl (CE or Cne), 2-trimethylsilylethyl, 2-nitroethyl, 2-sulfonylethyl, methyl, benzyl, o- nitrobenzyl, 2-(p-nitrophenyl)ethyl (NPE or Npe), 2-phenylethyl, 3-(N-tert-butylcarboxamido)-1-propyl, 4- oxopentyl, 4-methylthio-l-butyl, 2-cyano-1,1-dimethylethyl, 4-N-methylaminobutyl, 3-(2-pyridyl)-1-propyl, 2-[N-methyl-N-(2-pyridyl)]aminoethyl, 2-(N-formyl,N-methyl)aminoethyl, or 4-[N-methyl-N-(2,2,2- trifluoroacetyl)amino]butyl.

[0120] Protected thiols are well known in the art and include those described in detail in Greene (1999). Suitable protected thiols further include, but are not limited to, disulfides, thioethers, silyl thioethers, thioesters, thiocarbonates, and thiocarbamates, and the like. Examples of such groups include, but are not limited to, alkyl thioethers, benzyl and substituted benzyl thioethers, triphenylmethyl thioethers, and trichloroethoxycarbonyl thioester, to name but a few.

[0121] Reference: As used herein describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0122] Specificity: As is known in the art, “specificity” is a measure of the ability of a particular ligand (e.g., an agent) to distinguish its binding partner (e.g., beta-catenin) from other potential binding partners (e.g., another protein, another portion (e.g., domain) of beta-catenin.

[0123] Substitution: As described herein, compounds of the disclosure may contain optionally substituted and / or substituted moieties. In general, the term “substituted,” whether preceded by the term Page 42 of 884 12834799v1Attorney Docket Number: 2012675-0389 “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, example substituents are described below.

[0124] Suitable monovalent substituents are halogen; –(CH2)0–4R°; –(CH2)0–4OR°; −O(CH2)0-4Ro, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4Ph, which may be substituted with R°; −(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1- pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; – N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)N(R°)2; −N(R°)C(S)N(R°)2; –(CH2)0–4N(R°)C(O)OR°; – N(R°)N(R°)C(O)R°; −N(R°)N(R°)C(O)N(R°)2; −N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; –C(S)R°; – (CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSi(R°)3; –(CH2)0–4OC(O)R°; –OC(O)(CH2)0–4SR°, −SC(S)SR°; −(CH2)0–4SC(O)R°; –(CH2)0–4C(O)N(R°)2; –C(S)N(R°)2; –C(S)SR°; −SC(S)SR°, -(CH2)0–4OC(O)N(R°)2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; −C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; −S(O)2N(R°)2; -(CH2)0–4S(O)R°; –N(R°)S(O)2N(R°)2; – N(R°)S(O)2R°; –N(OR°)R°; −C(NH)N(R°)2; –Si(R°)3; –OSi(R°)3; −P(R°)2; −P(OR°)2; −OP(R°)2; −OP(OR°)2; −N(R°)P(R°)2; −B(R°)2; −OB(R°)2; −P(O)(R°)2; −OP(O)(R°)2; −N(R°)P(O)(R°)2; –(C1–4straight or branched alkylene)O–N(R°)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R°)2; wherein each R° may be substituted as defined below and is independently hydrogen, C1–10(e.g., C1–8, C1–6, C1–4, etc.) aliphatic, C1–10(e.g., C1–15, C1–10, C1–6, C1–4, etc.) heteroaliphatic having 1–5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, –CH2−(C6-10(e.g., C6, C10, etc.) aryl), – O(CH2)0–1(C6-10(e.g., C6, C10, etc.) aryl), −CH2-(5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered heteroaryl ring), a 3–10 (e.g., 3-, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered, monocyclic, bicyclic, or polycyclic, saturated, partially unsaturated or aryl ring having 0–5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–10 (e.g., 5-10, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered, monocyclic, bicyclic, or polycyclic, saturated, partially unsaturated or aryl ring having 0–5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, which may be substituted as defined below.

[0125] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, –(CH2)0–2R^, –(haloR^), Page 43 of 884 12834799v1Attorney Docket Number: 2012675-0389 –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2; –O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR^, –(CH2)0–2NR^2, –NO2, –SiR^3, –OSiR^3, -C(O)SR^, –(C1–4straight or branched alkylene)C(O)OR^, or –SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3–6 (e.g., 3-5, 5-6, etc.)–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0126] Suitable divalent substituents are the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as definednsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6 aliphatic whichmay be substituted as defined below, or an unsubstituted 3–6 (e.g., 3-5, 5-6, etc.)–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0127] Suitable substituents on the aliphatic group of R*are halogen, –R^, -(haloR^), –OH, −OR^, – O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3–6 (e.g., 3-5, 5-6, etc.)–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0128] In some embodiments, suitable substituents on a substitutable nitrogen are –R†, −NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, –S(O)2R†, –S(O)2NR†2, −C(S)NR†2, –C(NH)NR†2, or – N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 3–6 (e.g., 3-5, 5-6, etc.)–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12 (e.g., 3-10, 3-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0129] Suitable substituents on the aliphatic group of R†are independently halogen, −R^, -(haloR^), – OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3–6 (e.g., 3-5, 5-6, etc.)–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and Page 44 of 884 12834799v1Attorney Docket Number: 2012675-0389 sulfur.

[0130] Subject: As used herein, the term “subject” or “test subject” refers to any organism to which a provided compound or composition is administered in accordance with the present disclosure e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; etc.) and plants. In some embodiments, a subject may be suffering from, and / or susceptible to a disease, disorder, and / or condition. In some embodiments, a subject is a human.

[0131] Susceptible to: An individual who is “susceptible to” a disease, disorder, and / or condition is one who has a higher risk of developing the disease, disorder, and / or condition than does a member of the general public. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition may not have been diagnosed with the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may not exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will develop the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will not develop the disease, disorder, and / or condition.

[0132] Target polypeptide: A “target polypeptide”, as that term is used herein, is a polypeptide with which an agent interacts. In some embodiments, a target polypeptide is a beta-catenin polypeptide. In some embodiments, a target polypeptide comprises, consists essentially of, or is a binding site of beta-catenin polypeptide.

[0133] Target residue: A “target residue”, as that term is used herein, is a residue within a target polypeptide with which an agent is designed to interact. For example, an agent may be characterized by particular interaction motifs (e.g., aromatic groups as described herein) and / or residues (e.g., amino acid residues comprising aromatic groups as described herein) selected and arranged (by virtue of being presented on the selected scaffold) to be within a certain predetermined distance (or volume) of a target residue. In some embodiments, a target residue is or comprises an amino acid residue.

[0134] Therapeutic agent: As used herein, the phrase “therapeutic agent” refers to an agent that, when administered to a subject, has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect. In some embodiments, a therapeutic agent is any substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition.

[0135] Therapeutic regimen: A “therapeutic regimen”, as that term is used herein, refers to a dosing regimen whose administration across a relevant population may be correlated with a desired or beneficial therapeutic outcome.

[0136] Therapeutically effective amount: As used herein, the term “therapeutically effective amount” Page 45 of 884 12834799v1Attorney Docket Number: 2012675-0389 means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of compound in a formulation to treat a disease, disorder, and / or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and / or reduces incidence of one or more symptoms or features of the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.

[0137] Treat: As used herein, the term “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.

[0138] Unit dose: The expression “unit dose” as used herein refers to an amount administered as a single dose and / or in a physically discrete unit of a pharmaceutical composition. In many embodiments, a unit dose contains a predetermined quantity of an active agent. In some embodiments, a unit dose contains an entire single dose of the agent. In some embodiments, more than one unit dose is administered to achieve a total single dose. In some embodiments, administration of multiple unit doses is required, or expected to be required, in order to achieve an intended effect. A unit dose may be, for example, a volume of liquid (e.g., an acceptable carrier) containing a predetermined quantity of one or more therapeutic agents, a predetermined amount of one or more therapeutic agents in solid form, a sustained release formulation or drug delivery device containing a predetermined amount of one or more therapeutic agents, etc. It will be appreciated that a unit dose may be present in a formulation that includes any of a variety of components in addition to the therapeutic agent(s). For example, acceptable carriers (e.g., pharmaceutically acceptable carriers), diluents, stabilizers, buffers, preservatives, etc., may be included as described infra. It will be appreciated by those skilled in the art, in many embodiments, a total appropriate daily dosage of a particular therapeutic agent may comprise a portion, or a plurality, of unit doses, and may be decided, for example, by the attending physician within the scope of sound medical judgment. In some embodiments, the specific effective dose level for any particular subject or organism may depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active compound employed; specific composition employed; Page 46 of 884 12834799v1Attorney Docket Number: 2012675-0389 age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active compound employed; duration of the treatment; drugs and / or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.

[0139] Unsaturated: The term “unsaturated” as used herein, means that a moiety has one or more units of unsaturation.

[0140] Unless otherwise specified, salts, such as pharmaceutically acceptable acid or base addition salts, stereoisomeric forms, and tautomeric forms, of provided compound are included.

[0141] As those skilled in the art appreciate, many chemical elements have isotopes. For example, hydrogen (H) has two reported stable isotopes,1H (protium) and2H (deuterium, or D). Those skilled in the art appreciate that various isotopes may be present at one or more positions in structures described herein. For example, for hydrogen atoms in compounds, one or more may be1H and one or more may be2H. Some isotopes may have higher natural abundances than others, for example, the natural abundance of1H is higher than that of2H. In some embodiments, compounds or compositions comprise enriched levels of one or more isotopes. For example, in some embodiments, provided compounds or compositions comprise enriched levels of deuterium. Various technologies are available for incorporating enriched levels of isotopes and can be utilized in accordance with the present disclosure. In some embodiments, one or more isotopes at one or more positions in a compound are independently enriched, e.g., relative to natural abundances. In some embodiments, an enrichment is about or at least about 2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000 or 10000-fold (e.g., relative to natural abundance). In some embodiments, an enrichment for an isotope at a position is about or at least about 2-fold relative to natural abundance. In some embodiments, it is about or at least about 10-fold relative to natural abundance. In some embodiments, it is about or at least about 50-fold relative to natural abundance. In some embodiments, it is about or at least about 100-fold relative to natural abundance. In some embodiments, it is about or at least about 500-fold relative to natural abundance. In some embodiments, it is about or at least about 1000-fold relative to natural abundance. In some embodiments, an enrichment is such that about or at least about 1%, 2%, 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% of the molecules of the compound has a particular isotope at a particular position, wherein the percentage is higher than a reference (e.g., the percentage in an un-enriched preparation of the compound, natural abundance, the percentage at one or more unenriched positions, etc.). In some embodiments, a compound has an isotopic purity of about 5%-100% (e.g., about 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more, or about 5%-100%, 10%-100%, 20%-100%, 30%-100%, 50%-100%, 80%-100%, 90-100%, 95%-100%, 96%-100%, 97%-100%, 98%-100%, 99%-100%, 95-99%, 95%-99.5%, 95%-99.9%, etc.). In some embodiments, an isotopic purity is about 5%-100% (e.g., about 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more, or about 5%-100%, 10%-100%, 20%-100%, 30%-100%, 50%-100%, 80%-100%, 90-100%, 95%-100%, 96%-100%, 97%-100%, 98%-100%, 99%-100%, Page 47 of 884 12834799v1Attorney Docket Number: 2012675-0389 95-99%, 95%-99.5%, 95%-99.9%, etc.) with respect to an isotope at a position. For example, in some embodiments, a compound comprises one or more D at one or more positions, and for each D at a particular position, its isotopic purity is independently about 5%-100% (e.g., about 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more, or about 5%- 100%, 10%-100%, 20%-100%, 30%-100%, 50%-100%, 80%-100%, 90-100%, 95%-100%, 96%-100%, 97%-100%, 98%-100%, 99%-100%, 95-99%, 95%-99.5%, 95%-99.9%, etc.). In some embodiments, an isotopic purity is about 5% or more. In some embodiments, an isotopic purity is about 10% or more. In some embodiments, an isotopic purity is about 20% or more. In some embodiments, an isotopic purity is about 30% or more. In some embodiments, an isotopic purity is about 40% or more. In some embodiments, an isotopic purity is about 50% or more. In some embodiments, an isotopic purity is about 60% or more. In some embodiments, an isotopic purity is about 70% or more. In some embodiments, an isotopic purity is about 80% or more. In some embodiments, an isotopic purity is about 90% or more.

[0142] As used herein in the present disclosure, unless otherwise clear from context, (i) the term “a” or “an” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprising”, “comprise”, “including” (whether used with “not limited to” or not), and “include” (whether used with “not limited to” or not) may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; (iv) the term “another” may be understood to mean at least an additional / second one or more; (v) the terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (vi) where ranges are provided, endpoints are included. Certain Agents

[0143] In some embodiments, the present disclosure provides various agents. In some embodiments, the present disclosure provides an agent, wherein the agent has the structure of: TBM-L0-LBM, or a salt thereof, wherein: TBM is a target binding agent; L0is a covalent bond or an optionally substituted, bivalent C1-C30aliphatic or heteroaliphatic group having 1-12 heteroatoms, wherein one or more methylene units of the group are each optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, −C(O)O−, −(OCH2CH2)n−, or an amino acid residue; n is 1-20; and LBM is an E3 ubiquitin ligase binding moiety, or LBM is of formula II, III, IV, V, VI or VII: Page 48 of 884 12834799v1Attorney Docket Number: 2012675-0389 RRAnA wherein: Ring A1is an optionally substitute 3-30 mem ere rng having 0-10 heteroatoms; each RRAis independently R’; nA is 0, 1, 2, 3, or 4; rA is 0 or 1; LAis L; O O ZNH Z Nomeach Rais independently R’; each R’ is independently −R, −C(O)R, −CO2R, or −SO2R; each R is independently −H, or an optionally substituted group selected from C1-30aliphatic, C1-30heteroaliphatic having 1-10 heteroatoms, C6-30aryl, C6-30arylaliphatic, C6-30arylheteroaliphatic having 1-10 heteroatoms, 5-30 membered heteroaryl having 1-10 heteroatoms, and 3-30 membered heterocyclyl having 1- 10 heteroatoms; or two R groups are optionally and independently taken together to form a covalent bond, or: two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered ring having, in addition to the atom, 0-10 heteroatoms; or two or more R groups on two or more atoms are optionally and independently taken together with their intervening atom(s) to form an optionally substituted, 3-30 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms; each L is independently a covalent bond or an optionally substituted bivalent C1-C6aliphatic or heteroaliphatic group having 1-10 heteroatoms, wherein one or more methylene units of the group are Page 49 of 884 12834799v1Attorney Docket Number: 2012675-0389 optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−; and each −Cy− is independently an optionally substituted bivalent 3-30 membered ring having 0-10 heteroatoms;-- (RRC)nC(RRD)nD LCDwherein: Ring B, Ring C, and Ring D are each independently an optionally substituted 3-30 membered ring having 0-10 heteroatoms; RBis R’; LB, LBC, and LCDare each independently L; each RRBis independently −OR’ or R’; each RRCis independently R’; each RRDis independently R’; and each of nB, nC and nD is independently 0, 1, 2, 3, or 4; RIVH Owherein RIVis R’; LERFLEF12834799v1Attorney Docket Number: 2012675-0389 V, wherein: LE, LEF, and LGHare each independently L; Ring E, Ring F, Ring G, and Ring H are each independently an optionally substituted 3-30 membered ring having 0-10 heteroatoms; each of RRE, RRF, RRG, and RRHis independently R’; andeach of nE, nF, nG, and nH is independently 0, 1, 2, 3, or 4; O (RRJ)nJ Jwherein:Ring J is an optionally substituted 3-30 membered ring having 0-10 heteroatoms; each RRJis independently R’; and nJ is 0, 1, 2, 3, or 4; (RRL)nL L wherein:Ring K and Ring L are each independently an optionally substituted 3-30 membered ring having 0-10 heteroatoms; LKLis L; each of RRKand RRLis independently R’; and each of nK and nL is independently 0, 1, 2, 3, or 4; O H O N H, wherein RVIIIis R’; and Page 51 of 884 12834799v1Attorney Docket Number: 2012675-0389 O H ;

[0144] In some embodiments,an agent compr ses a target n ng moiety, a linker, and an E3 ubiquitin ligase binding moiety. In some embodiments, a target binding moiety is or comprises a stapled peptide moiety. In some embodiments, a target binding moiety can bind to beta-catenin. In some embodiments, a target binding moiety is –[PTBM], wherein PTBMis or comprises a peptide. In some embodiments, a target binding moiety is –[PTBM], wherein PTBMis or comprises a stapled peptide. In some embodiments, PTBMcan bind beta-catenin.

[0145] In some embodiments, an agent can provide different properties and / or activities compared to a reference agent. In some embodiments, an agent can provide improved properties and / or activities compared to a reference agent. In some embodiments, a reference agent is an otherwise identical agent but without linker and / or E3 ubiquitin ligase binding moiety. In some embodiments, a reference agent has the structure of TBM-L0-H or a salt thereof. In some embodiments, a reference agent has the structure of TBM-H or a salt thereof. In some embodiments, a target binding moiety in an agent is –[PTBM]. In some embodiments, a reference agent is PTBM. In some embodiments, a reference agent is [PTBM]−L0−H.

[0146] In some embodiments, LBM is an E3 ubiquitin ligase binding moiety. In some embodiments, LBM can bind an E3 ubiquitin ligase. In some embodiments, in a reference agent LBM cannot bind an E3 ubiquitin ligase that an agent can bind.

[0147] Various embodiments of agents, target binding moieties, linkers, E3 ubiquitin ligase binding moieties, TBM, L0, LBM and methods thereof are described herein as examples. Target Binding Moieties

[0148] In some embodiments, provided technologies comprise target binding moieties. For example, in various agent having the structure of TBM-L0-LBM, TBM is a target binding moiety. Among other things, target binding moieties can bind target agents, e.g., a beta-catenin polypeptide, and can promote delivery of agents comprising target binding moieties to targets that comprise or express target agents that target binding moieties can bind. In some embodiments, a target binding moiety can bind to a target agent which is or comprise a polypeptide. In some embodiments, a target binding moiety can bind to a target agent which is or comprise a beta-catenin polypeptide. In some embodiments, a beta-catenin polypeptide is or comprises SEQ ID NO: 1 or a portion thereof. In some embodiments, a beta-catenin polypeptide is or comprises residues 250-450 of SEQ ID NO: 1. In some embodiments, a beta-catenin polypeptide is or comprises residues 305- Page 52 of 884 12834799v1Attorney Docket Number: 2012675-0389 419 of SEQ ID NO: 1.

[0149] In some embodiments, a target binding moiety is or comprises –[PTBM]. In some embodiments, a target binding moiety is –[PTBM]. In some embodiments, PTBMis or comprises a peptide. In some embodiments, PTBMis a peptide. In some embodiments, PTBMis or comprise a stapled peptide. In some embodiments, PTBMis a stapled peptide. In some embodiments, PTBMis or comprises a stitched peptide. In some embodiments, PTBMis a stitched peptide. In some embodiments, PTBMcomprises a N-terminus group and / or C-terminus group as described herein. Certain embodiments of peptides, including stapled peptides, are described herein as examples. Peptides

[0150] In some embodiments, a provided agent is or comprises a peptide. In some embodiments, a provided agent is a peptide. In some embodiments, PTBMis a peptide. In some embodiments, a peptide is a stapled peptide. In some embodiments, a provided agent is a stapled peptide. In some embodiments, PTBMis a stapled peptide. In some embodiments, a peptide is a stitched peptide. In some embodiments, a provided agent is a stitched peptide. In some embodiments, PTBMis a stitched peptide. In some embodiments, a stitched peptide comprises two or more staples, wherein two staples are bonded to the same peptide backbone atom. Stapled peptides as described herein are typically peptides in which two or more amino acids of a peptide chain are linked through connection of two peptide backbone atoms of the amino acid residues and, as is understood by those skilled in the art, the connection is not through the peptide backbone between the linked amino acid residues. In some embodiments, a staple as described herein is a linker that link one amino acid residue to another amino acid residue, e.g., through bonding to a peptide backbone atom of each of the amino acid residues and, as is understood by those skilled in the art, the connection through a staple is not through the peptide backbone between the linked amino acid residues. In some embodiments, a staple bonds to the peptide backbone by replacing one or more hydrogen and / or substituents (e.g., side chains, O, S, etc.) on peptide backbone atoms (e.g., C, N, etc.). In some embodiments, side chains form portions of staples. In some embodiments, a staple is bonded to two carbon backbone atoms, e.g., two alpha carbon atoms. In some embodiments, a staple comprises C(R’)2or N(R’), either individually or as part of a large moiety, wherein R’ is R and is taken together with another group attached to a backbone atom which can be R (e.g., Ra3) and their intervening atoms to form a ring as described herein (e.g., when PyrS2 is stapled in various peptides).

[0151] In some embodiments, a stapled peptide comprises one or more staples. In some embodiments, a stapled peptide comprises two or more staples. In some embodiments, a stapled peptide comprises three or more staples. In some embodiments, a stapled peptide comprises four or more staples. In some embodiments, there are three staples in a stapled peptide. In some embodiments, there are four staples in a stapled peptide.

[0152] As will be appreciated by those of ordinary skill in the art, a variety of peptide stapling technologies are available, including both hydrocarbon-stapling and non-hydrocarbon-stapling technologies, and can be utilized in accordance with the present disclosure. Various technologies for stapled and stitched Page 53 of 884 12834799v1Attorney Docket Number: 2012675-0389 peptides, including various staples and / or methods for manufacturing are available and may be utilized in accordance with the present disclosure, e.g., those described in WO 2019 / 051327 and WO 2020 / 041270, the staples of each of which are incorporated herein by reference.

[0153] In some embodiments, a peptide, e.g., a stapled peptide, is or comprise a helical structure. In some embodiments, a peptide is a stapled peptide.

[0154] In some embodiments, a staple is a hydrocarbon staple. In some embodiments, a staple as described herein is a non-hydrocarbon staple. In some embodiments, a non-hydrocarbon staple comprises one or more chain heteroatoms wherein a chain of a staple is the shortest covalent connection within the staple from one end of the staple to the other end of the staple. In some embodiments, a non-hydrocarbon staple is or comprises at least one sulfur atom derived from an amino acid residue of a polypeptide. In some embodiments, a non-hydrocarbon staple comprises two sulfur atom derived from two different amino acid residues of a polypeptide. In some embodiments, a non-hydrocarbon staple comprises two sulfur atoms derived from two different cysteine residues of a polypeptide. In some embodiments, a staple is a cysteine staple. In some embodiments, a staple is a non-cysteine staple. In some embodiments, a non-hydrocarbon staple is a carbamate staple and comprises a carbamate moiety (e.g., −N(R’)−C(O)−O−) in its chain. In some embodiments, a non-hydrocarbon staple is an amino staple and comprises an amino group (e.g., −N(R’)−) in its chain. In some embodiments, an amino group in an amino staple, e.g., (−N(R’)−) is not bonded to a carbon atom that additionally forms a double bond with a heteroatom (e.g., −C(=O), −C(=S), −C(=N−R’), etc.) so that it is not part of another nitrogen-containing group such as amide, carbamate, etc. In some embodiments, a non-hydrocarbon staple is an ester staple and comprises an ester moiety (−C(O)−O−) in its chain. In some embodiments, a non-hydrocarbon staple is an amide staple and comprises an amide moiety (−C(O)−N(R’)−) in its chain. In some embodiments, a non-hydrocarbon staple is a sulfonamide staple and comprises a sulfonamide moiety (−S(O)2−N(R’)−) in its chain. In some embodiments, a non-hydrocarbon staple is an ether staple and comprises an ether moiety (−O−) in its chain. In some embodiments, R’ of a carbamate moiety, amino group, amide moiety, sulfonamide moiety, or ether moiety is R, and is taken together with an R group attached to a backbone (e.g., Ra3when it is R) and their intervening atoms to form a ring as described herein. In some embodiments, R’ of a carbamate moiety or amino group is R, and is taken together with an R group attached to a backbone (e.g., Ra3when it is R) and their intervening atoms to form a ring as described herein.

[0155] In some embodiments, a staple comprises one or more amino groups, e.g., −N(R’)−, wherein each R’ is independently as described herein. In some embodiments, −N(R’)− bonds to two carbon atoms. In some embodiments, −N(R’)− bonds to two carbon atoms, wherein neither of the two carbon atoms are bond to any heteroatoms through a double bond. In some embodiments, −N(R’)− bonds to two sp3 carbon atoms. In some embodiments, a staple comprises one or more −C(O)−N(R’)− groups, wherein each R’ is independently as described herein. In some embodiments, a staple comprises one or more carbamate groups, e.g., one or more −(O)−C(O)−N(R’)−, wherein each R’ is independently as described herein. In some Page 54 of 884 12834799v1Attorney Docket Number: 2012675-0389 embodiments, R’ is −H. In some embodiments, R’ is optionally substituted C1-6aliphatic. In some embodiments, R’ is optionally substituted C1-6alkyl. In some embodiments, R’ is C1-6aliphatic. In some embodiments, R’ is C1-6alkyl. In some embodiments, R’ is methyl.

[0156] In some embodiments, a stapled peptide comprise one or more staples. In some embodiments, a stapled peptide comprises one and no more than one staple. In some embodiments, a stapled peptide comprises two and no more than two staples. In some embodiments, two staples of a stapled peptide bond to a common backbone atom. In some embodiments, two staples of a stapled peptide bond to a common backbone atom which is an alpha carbon atom of an amino acid residue. In some embodiments, a stapled peptide comprises three or more staples. In some embodiments, a stapled peptides comprise four or more staples. In some embodiments, a stapled peptide comprises three and no more than three staples. In some embodiments, a stapled peptide comprises four and no more than four staples. In some embodiments, each staple independently has the structure of −Ls1−Ls2−Ls3− as described herein. In some embodiments, each staple is independently bonded to two amino acid residues. In some embodiments, each staple is independently bonded to two alpha carbon atoms.

[0157] In some embodiments, two, three, four, or all staples of a stapled peptide are within a region that has a length of several amino acid residues. In some embodiments, two staples are within such a region. In some embodiments, three staples are within such a region. In some embodiments, four staples are within such a region. In some embodiments, all staples are within such a region. In some embodiments, a region has a length of 5-20, 5-15, 5-14, 5-113, 5-12, 5-11, 5-10, 6-20, 6-15, 6-14, 6-113, 6-12, 6-11, 6-10, 7-20, 7-15, 7- 14, 7-113, 7-12, 7-11, 7-10, 10-16, 10-15, 10-14, 11-16, 11-15, 11-14, 12-16, 12-15, 12-14, 13-15 or 13-14 amino acid residues. In some embodiments, a region has a length of 5 amino acid residues. In some embodiments, a region has a length of 6 amino acid residues. In some embodiments, a region has a length of 7 amino acid residues. In some embodiments, a region has a length of 8 amino acid residues. In some embodiments, a region has a length of 9 amino acid residues. In some embodiments, a region has a length of 10 amino acid residues. In some embodiments, a region has a length of 11 amino acid residues. In some embodiments, a region has a length of 12 amino acid residues. In some embodiments, a region has a length of 13 amino acid residues. In some embodiments, a region has a length of 14 amino acid residues. In some embodiments, a region has a length of 15 amino acid residues. In some embodiments, a region has a length of 16 amino acid residues. In some embodiments, a region has a length of 17 amino acid residues. In some embodiments, a region has a length of 18 amino acid residues. In some embodiments, a region has a length of 19 amino acid residues. In some embodiments, a region has a length of 20 amino acid residues. For example, in various embodiments, stapled peptides comprise three staples within in a region of 14 amino acids (e.g., a staple bonded to aa1 and aa4, a staple bonded to aa4 and aa11, and a staple bonded to aa10 and aa14).

[0158] In some embodiments, peptides, e.g., staple peptides, of the present disclosure is or comprises a helix structure. As those skilled in the art will appreciate, helixes can have various lengths. In some embodiments, lengths of helixes range from 5 to 30 amino acid residues. In some embodiments, a length of a Page 55 of 884 12834799v1Attorney Docket Number: 2012675-0389 helix is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or more, amino acid residues. In some embodiments, a length of a helix is 6 amino acid residues. In some embodiments, a length of a helix is 8 amino acid residues. In some embodiments, a length of a helix is 10 amino acid residues. In some embodiments, a length of a helix is 12 amino acid residues. In some embodiments, a length of a helix is 14 amino acid residues. In some embodiments, a length of a helix is 16 amino acid residues. In some embodiments, a length of a helix is 17 amino acid residues. In some embodiments, a length of a helix is 18 amino acid residues. In some embodiments, a length of a helix is 19 amino acid residues. In some embodiments, a length of a helix is 20 amino acid residues.

[0159] Amino acids stapled together can have various number of amino acid residues in between, e.g., 1- 20, 1-15, 1-10, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, etc. In some embodiments, a staple is (i, i+4) which means there are three amino acid residues between the two amino acids (at positions i and i+4, respectively) that bond to the staple (at positions i+1, i+2, i+3, respectively). In some embodiments, a staple is (i, i+2). In some embodiments, a staple is (i, i+3). In some embodiments, a staple is (i, i+5). In some embodiments, a staple is (i, i+6). In some embodiments, a staple is (i, i+7). In some embodiments, a staple is (i, i+8). In some embodiments, a stapled peptide comprises two staples, one is (i, i+2) and the other is (i, i+7). In some embodiments, a stapled peptide comprises two staples, one is (i, i+3) and the other is (i, i+7). In some embodiments, a stapled peptide comprises two staples, one is (i, i+3) and the other is (i, i+4). In some embodiments, a stapled peptide comprises two staples, one is (i, i+4) and the other is (i, i+7). In some embodiments, a stapled peptide comprises two staples, one is (i, i+3) and the other is (i, i+3). In some embodiments, a stapled peptide comprises two staples, one is (i, i+4) and the other is (i, i+4). In some embodiments, a stapled peptide comprises two staples, one is (i, i+7) and the other is (i, i+7). In some embodiments, the two staples are bonded to a common backbone atom, e.g., an alpha carbon atom of an amino acid residue. In some embodiments, a stapled peptide further comprises a third staple. In some embodiments, a third staple is (i, i+3). In some embodiments, a third staple is (i, i+4). In some embodiments, a third staple is (i, i+7). In some embodiments, a stapled peptide further comprises a fourth staple. In some embodiments, a fourth staple is (i, i+3). In some embodiments, a fourth staple is (i, i+4). In some embodiments, a fourth staple is (i, i+7).

[0160] In some embodiments, a stapled peptide comprises a staple which staple is Ls, wherein Lsis −Ls1−Ls2−Ls3−, each of Ls1, Ls2, and Ls3is independently L, wherein each L is independently as described in the present disclosure. In some embodiments, a provided staple is Ls.

[0161] In some embodiments, Ls1comprises at least one −N(R’)−, wherein R’ is as described in the present disclosure. In some embodiments, the −N(R’)− is bonded to two carbon atoms, wherein neither of the two carbon atoms forms a double bond with a heteroatom. In some embodiments, the −N(R’)− is not bonded to −C(O)−. In some embodiments, the −N(R’)− is not bonded to −C(S)−. In some embodiments, the −N(R’)− is not bonded to −C(=NR’)−. In some embodiments, Ls1is −L’−N(R’)−, wherein L’ is optionally substituted bivalent C1-C19aliphatic. In some embodiments, Ls1is −L’−N(CH3)−, wherein L’ is optionally substituted Page 56 of 884 12834799v1Attorney Docket Number: 2012675-0389 bivalent C1-C19aliphatic.

[0162] In some embodiments, R’ is optionally substituted C1-6alkyl. In some embodiments, R’ is C1-6alkyl. In some embodiments, R’ is methyl. In some embodiments, the peptide backbone atom to which Ls1is bonded is also bonded to R1, and R’ and R1are both R and are taken together with their intervene atoms to form an optionally substituted ring as described in the present disclosure. In some embodiments, a formed ring has no additional ring heteroatoms in addition to the nitrogen atom to which R’ is bonded. In some embodiments, a formed ring is 3-membered. In some embodiments, a formed ring is 4-membered. In some embodiments, a formed ring is 5-membered. In some embodiments, a formed ring is 6-membered.

[0163] In some embodiments, L’ is optionally substituted bivalent C1-C20aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C19aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C15aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C10aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C9aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C8aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C7aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C6aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C5aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C4aliphatic. In some embodiments, L’ is optionally substituted alkylene. In some embodiments, L’ is optionally substituted alkenylene. In some embodiments, L’ is unsubstituted alkylene. In some embodiments, L’ is −CH2−. In some embodiments, L’ is −(CH2)2−. In some embodiments, L’ is −(CH2)3−. In some embodiments, L’ is −(CH2)4−. In some embodiments, L’ is −(CH2)5−. In some embodiments, L’ is −(CH2)6−. In some embodiments, L’ is −(CH2)7−. In some embodiments, L’ is −(CH2)8−. In some embodiments, L’ is bonded to a peptide backbone atom. In some embodiments, L’ is optionally substituted alkenylene. In some embodiments, L’ is unsubstituted alkenylene. In some embodiments, L’ is −CH2−CH=CH−CH2−.

[0164] In some embodiments, L’ is optionally substituted phenylene.

[0165] In some embodiments, Ls1comprises at least one −N(R’)C(O)−, wherein R’ is as described in the present disclosure. In some embodiments, Ls1is −L’−N(R’)C(O)−, wherein each of L’ and R’ is independently as described in the present disclosure. In some embodiments, Ls1is −L’−N(CH3)C(O)−, wherein L’ is independently as described in the present disclosure.

[0166] In some embodiments, Ls1comprises at least one −C(O)O−. In some embodiments, Ls1comprises at least one −C(O)O−. In some embodiments, Ls1is −L’−C(O)O− or −L’−OC(O)−, wherein each L’ is independently as described in the present disclosure. In some embodiments, Ls1is −L’−C(O)O−, wherein each L’ is independently as described in the present disclosure. In some embodiments, Ls1is −L’−OC(O)−, wherein each L’ is independently as described in the present disclosure.

[0167] In some embodiments, Ls1comprises at least one −S(O)2−N(R’)−, wherein R’ is as described in the present disclosure. In some embodiments, Ls1comprises at least one −S(O)2−N(R’)−, wherein R’ is as described in the present disclosure. In some embodiments, Ls1is −L’−N(R’)−S(O)2− or −L’−S(O)2−N(R’)−, Page 57 of 884 12834799v1Attorney Docket Number: 2012675-0389 wherein each of L’ and R’ is independently as described in the present disclosure. In some embodiments, Ls1is −L’−N(R’)−S(O)2−, wherein each of L’ and R’ is independently as described in the present disclosure. In some embodiments, Ls1is −L’−S(O)2−N(R’)−, wherein each of L’ and R’ is independently as described in the present disclosure. In some embodiments, Ls1is −L’−N(CH3)−S(O)2− or −L’−S(O)2−N(CH3)−, wherein each L’ is independently as described in the present disclosure. In some embodiments, Ls1is −L’−N(CH3)−S(O)2−, wherein L’ is as described in the present disclosure. In some embodiments, Ls1is −L’−S(O)2−N(CH3)−, wherein L’ is as described in the present disclosure.

[0168] In some embodiments, Ls1comprises at least one −O−. In some embodiments, Ls1is −L’−O−, wherein L’ is independently as described in the present disclosure.

[0169] In some embodiments, Ls1is a covalent bond.

[0170] In some embodiments, Ls1is L’, wherein L’ is as described in the present disclosure.

[0171] In some embodiments, Ls2is L, wherein L is as described in the present disclosure. In some embodiments, Ls2is L’, wherein L’ is as described in the present disclosure. In some embodiments, Ls2comprises −CH2−CH=CH−CH2−. In some embodiments, Ls2is −CH2−CH=CH−CH2−. In some embodiments, Ls2comprises −(CH2)4−. In some embodiments, Ls2is −(CH2)4−.

[0172] In some embodiments, Ls3comprises at least one −N(R’)−, wherein R’ is as described in the present disclosure. In some embodiments, the −N(R’)− is bonded to two carbon atoms, wherein neither of the two carbon atoms forms a double bond with a heteroatom. In some embodiments, the −N(R’)− is not bonded to −C(O)−. In some embodiments, the −N(R’)− is not bonded to −C(S)−. In some embodiments, the −N(R’)− is not bonded to −C(=NR’)−. In some embodiments, Ls3is −L’−N(R’)−, wherein L’ is optionally substituted bivalent C1-C19aliphatic. In some embodiments, Ls3is −L’−N(CH3)−, wherein L’ is optionally substituted bivalent C1-C19aliphatic.

[0173] In some embodiments, Ls3comprises at least one −N(R’)C(O)−, wherein R’ is as described in the present disclosure. In some embodiments, Ls3is −L’−N(R’)C(O)−, wherein each of L’ and R’ is independently as described in the present disclosure. In some embodiments, Ls3is −L’−N(CH3)C(O)−, wherein L’ is independently as described in the present disclosure.

[0174] In some embodiments, Ls3comprises at least one −C(O)O−. In some embodiments, Ls3comprises at least one −C(O)O−. In some embodiments, Ls3is −L’−C(O)O− or −L’−OC(O)−, wherein each L’ is independently as described in the present disclosure. In some embodiments, Ls3is −L’−C(O)O−, wherein each L’ is independently as described in the present disclosure. In some embodiments, Ls3is −L’−OC(O)−, wherein each L’ is independently as described in the present disclosure.

[0175] In some embodiments, Ls3comprises at least one −S(O)2−N(R’)−, wherein R’ is as described in the present disclosure. In some embodiments, Ls3comprises at least one −S(O)2−N(R’)−, wherein R’ is as described in the present disclosure. In some embodiments, Ls3is −L’−N(R’)−S(O)2− or −L’−S(O)2−N(R’)−, wherein each of L’ and R’ is independently as described in the present disclosure. In some embodiments, Ls3is −L’−N(R’)−S(O)2−, wherein each of L’ and R’ is independently as described in the present disclosure. In Page 58 of 884 12834799v1Attorney Docket Number: 2012675-0389 some embodiments, Ls3is −L’−S(O)2−N(R’)−, wherein each of L’ and R’ is independently as described in the present disclosure. In some embodiments, Ls3is −L’−N(CH3)−S(O)2− or −L’−S(O)2−N(CH3)−, wherein each L’ is independently as described in the present disclosure. In some embodiments, Ls3is −L’−N(CH3)−S(O)2−, wherein L’ is as described in the present disclosure. In some embodiments, Ls3is −L’−S(O)2−N(CH3)−, wherein L’ is as described in the present disclosure.

[0176] In some embodiments, Ls3comprises at least one −O−. In some embodiments, Ls3is −L’−O−,wherein L’ is independently as described in the present disclosure.

[0177] In some embodiments, Ls3is L’, wherein L’ is as described in the present disclosure. In some embodiments, Ls3is optionally substituted alkylene. In some embodiments, Ls3is unsubstituted alkylene.

[0178] In some embodiments, Lscomprises at least one −N(R’)−, wherein R’ is as described in the present disclosure. In some embodiments, the −N(R’)− is bonded to two carbon atoms, wherein neither of the two carbon atoms forms a double bond with a heteroatom. In some embodiments, the −N(R’)− is not bonded to −C(O)−. In some embodiments, the −N(R’)− is not bonded to −C(S)−. In some embodiments, the −N(R’)− is not bonded to −C(=NR’)−. In some embodiments, Lscomprises at least one −N(R’)C(O)−, wherein R’ is as described in the present disclosure.

[0179] In some embodiments, Ls, Ls1, Ls2, and Ls3each independently and optionally comprise a R’ group, e.g., a R’ group in −C(R’)2−, −N(R’)−, etc., and the R’ group is taken with a group (e.g., a group that can be R) attached to a backbone atom (e.g., Ra1, Ra2, Ra3, a R’ group of La1or La2(e.g., a R’ group in −C(R’)2−, −N(R’)−, etc.), etc.) to form a double bond or an optionally substituted ring as two R groups can. In some embodiments, a formed ring is an optionally substituted 3-10 membered ring. In some embodiments, a formed ring is an optionally substituted 3-membered ring. In some embodiments, a formed ring is an optionally substituted 4-membered ring. In some embodiments, a formed ring is an optionally substituted 5- membered ring. In some embodiments, a formed ring is an optionally substituted 6-membered ring. In some embodiments, a formed ring is monocyclic. In some embodiments, a formed ring is saturated. In some embodiments, a formed ring is partially unsaturated. In some embodiments, a formed ring is aromatic. In some embodiments, a formed ring comprises one or more ring heteroatom (e.g., nitrogen). In some embodiments, a staple, or Ls, Ls1, Ls2, and / or Ls3comprises −N(R’)−, and the R’ is taken together with a group attached to a backbone atom to form an optionally substituted ring as described herein. In some embodiments, a staple, or Ls, Ls1, Ls2, and / or Ls3comprises −C(R’)2−, and the R’ is taken together with a group attached to a backbone atom to form an optionally substituted ring as described herein.

[0180] In some embodiments, a staple, or Ls, Ls1, Ls2, and / or Ls3comprises portions of one or more amino acid side chains (e.g., a side chain other than its terminal =CH2).

[0181] As will be clear to those skilled in the art reading the present disclosure, the letter “L” is used to refer to a linker moiety as described herein; each Lsuperscript(e.g., La, Ls1, Ls2, Ls3, Ls, etc.) therefore is understood, in some embodiments, to be L, unless otherwise specified.

[0182] In some embodiments, L comprises at least one −N(R’)−, wherein R’ is as described in the Page 59 of 884 12834799v1Attorney Docket Number: 2012675-0389 present disclosure. In some embodiments, the −N(R’)− is bonded to two carbon atoms, wherein neither of the two carbon atoms forms a double bond with a heteroatom. In some embodiments, the −N(R’)− is not bonded to −C(O)−. In some embodiments, the −N(R’)− is not bonded to −C(S)−. In some embodiments, the −N(R’)− is not bonded to −C(=NR’)−. In some embodiments, L is −L’−N(R’)−, wherein L’ is optionally substituted bivalent C1-C19aliphatic. In some embodiments, L is −L’−N(CH3)−, wherein L’ is optionally substituted bivalent C1-C19 aliphatic.

[0183] In some embodiments, L comprises at least one −N(R’)C(O)−, wherein R’ is as described in the present disclosure. In some embodiments, L is −L’−N(R’)C(O)−, wherein each of L’ and R’ is independently as described in the present disclosure. In some embodiments, L is −L’−N(CH3)C(O)−, wherein L’ is independently as described in the present disclosure.

[0184] In some embodiments, L comprises at least one −C(O)O−. In some embodiments, L comprises at least one −C(O)O−. In some embodiments, L is −L’−C(O)O− or −L’−OC(O)−, wherein each L’ is independently as described in the present disclosure. In some embodiments, L is −L’−C(O)O−, wherein each L’ is independently as described in the present disclosure. In some embodiments, L is −L’−OC(O)−, wherein each L’ is independently as described in the present disclosure.

[0185] In some embodiments, L comprises at least one −S(O)2−N(R’)−, wherein R’ is as described in the present disclosure. In some embodiments, L comprises at least one −S(O)2−N(R’)−, wherein R’ is as described in the present disclosure. In some embodiments, L is −L’−N(R’)−S(O)2− or −L’−S(O)2−N(R’)−, wherein each of L’ and R’ is independently as described in the present disclosure. In some embodiments, L is −L’−N(R’)−S(O)2−, wherein each of L’ and R’ is independently as described in the present disclosure. In some embodiments, L is −L’−S(O)2−N(R’)−, wherein each of L’ and R’ is independently as described in the present disclosure. In some embodiments, L is −L’−N(CH3)−S(O)2− or −L’−S(O)2−N(CH3)−, wherein each L’ is independently as described in the present disclosure. In some embodiments, L is −L’−N(CH3)−S(O)2−, wherein L’ is as described in the present disclosure. In some embodiments, L is −L’−S(O)2−N(CH3)−, wherein L’ is as described in the present disclosure.

[0186] In some embodiments, L comprises at least one −O−. In some embodiments, L is −L’− O−, wherein L’ is independently as described in the present disclosure.

[0187] In some embodiments, L is L’, wherein L’ is as described in the present disclosure. In some embodiments, L is optionally substituted alkylene. In some embodiments, L is unsubstituted alkylene.

[0188] In some embodiments, L is optionally substituted bivalent C1-C25aliphatic. In some embodiments, L is optionally substituted bivalent C1-C20aliphatic. In some embodiments, L is optionally substituted bivalent C1-C15aliphatic. In some embodiments, L is optionally substituted bivalent C1-C10aliphatic. In some embodiments, L is optionally substituted bivalent C1-C9aliphatic. In some embodiments, L is optionally substituted bivalent C1-C8aliphatic. In some embodiments, L is optionally substituted bivalent C1-C7aliphatic. In some embodiments, L is optionally substituted bivalent C1-C6aliphatic. In some embodiments, L is optionally substituted bivalent C1-C5aliphatic. In some embodiments, L is optionally Page 60 of 884 12834799v1Attorney Docket Number: 2012675-0389 substituted bivalent C1-C4aliphatic. In some embodiments, L is optionally substituted alkylene. In some embodiments, L is optionally substituted alkenylene. In some embodiments, L is unsubstituted alkylene. In some embodiments, L is −CH2−. In some embodiments, L is −(CH2)2−. In some embodiments, L is −(CH2)3−. In some embodiments, L is −(CH2)4−. In some embodiments, L is −(CH2)5−. In some embodiments, L is −(CH2)6−. In some embodiments, L is −(CH2)7−. In some embodiments, L is −(CH2)8−. In some embodiments, L is bonded to a peptide backbone atom. In some embodiments, L is optionally substituted alkenylene. In some embodiments, L is unsubstituted alkenylene. In some embodiments, L is −CH2−CH=CH−CH2−.

[0189] In some embodiments, one end of a staple is connected to an atom An1of the peptide backbone, wherein An1is optionally substituted with R1and is an atom of an amino acid residue at amino acid position n1of the peptide from the N-terminus, and the other end is connected to an atom An2of the peptide backbone, wherein An2is optionally substituted with R2(in some embodiments, R1and / or R2is R which can be hydrogen) and is an atom of an amino acid residue at amino acid position n2of the peptide from the N- terminus, wherein each of n1and n2is independently an integer, and n2= n1+ m, wherein m is 3-12.

[0190] In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some embodiments, m is 11. In some embodiments, a staple is referred to a (i, i+m) staple.

[0191] In some embodiments, An1is a carbon atom. In some embodiments, An1is achiral. In some embodiments, An1is chiral. In some embodiments, An1is R. In some embodiments, An1is S.

[0192] In some embodiments, An2is a carbon atom. In some embodiments, An2is achiral. In some embodiments, An2is chiral. In some embodiments, An2is R. In some embodiments, An2is S.

[0193] In some embodiments, An1is achiral and An2is achiral. In some embodiments, An1is achiral and An2is R. In some embodiments, An1is achiral and An2is S. In some embodiments, An1is R and An2is achiral. In some embodiments, An1is R and An2is R. In some embodiments, An1is R and An2is S. In some embodiments, An1is S and An2is achiral. In some embodiments, An1is S and An2is R. In some embodiments, An1is S and An2is S.

[0194] In some embodiments, provided stereochemistry at staple-backbone connection points and / or combinations thereof, optionally together with one or more structural elements of provided peptide, e.g., staple chemistry (hydrocarbon, non-hydrocarbon), staple length, etc. can provide various benefits, such as improved preparation yield, purity, and / or selectivity, improved properties (e.g., improved solubility, improved stability, lowered toxicity, improved selectivity, etc.), improved activities, etc. In some embodiments, provided stereochemistry and / or stereochemistry combinations are different from those typically used, e.g., those of US 9617309, US 2015-0225471, US 2016-0024153, US 2016-0215036, US 2016-0244494, WO 2017 / 062518, and provided one or more of benefits described in the present disclosure.

[0195] In some embodiments, a staple can be of various lengths, in some embodiments, as represent by Page 61 of 884 12834799v1Attorney Docket Number: 2012675-0389 the number of chain atoms of a staple. In some embodiments, a chain of a staple is the shortest covalent connection in the staple from a first end (connection point with a peptide backbone) of a staple to a second end of the staple, wherein the first end and the second end are connected to two different peptide backbone atoms. In some embodiments, a staple comprises 5-30 chain atoms, e.g., 5-20, 5-15, 5, 6, 7, 8, 9, or 10 to 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 chain atoms. In some embodiments, a staple comprises 5 chain atoms. In some embodiments, a staple comprises 6 chain atoms. In some embodiments, a staple comprises 7 chain atoms. In some embodiments, a staple comprises 8 chain atoms. In some embodiments, a staple comprises 9 chain atoms. In some embodiments, a staple comprises 10 chain atoms. In some embodiments, a staple comprises 11 chain atoms. In some embodiments, a staple comprises 12 chain atoms. In some embodiments, a staple comprises 13 chain atoms. In some embodiments, a staple comprises 14 chain atoms. In some embodiments, a staple comprises 15 chain atoms. In some embodiments, a staple comprises 16 chain atoms. In some embodiments, a staple comprises 17 chain atoms. In some embodiments, a staple comprises 18 chain atoms. In some embodiments, a staple comprises 19 chain atoms. In some embodiments, a staple comprises 20 chain atoms. In some embodiments, a staple has a length of 5 chain atoms. In some embodiments, a staple has a length of 6 chain atoms. In some embodiments, a staple has a length of 7 chain atoms. In some embodiments, a staple has a length of 8 chain atoms. In some embodiments, a staple has a length of 9 chain atoms. In some embodiments, a staple has a length of 10 chain atoms. In some embodiments, a staple has a length of 11 chain atoms. In some embodiments, a staple has a length of 12 chain atoms. In some embodiments, a staple has a length of 13 chain atoms. In some embodiments, a staple has a length of 14 chain atoms. In some embodiments, a staple has a length of 15 chain atoms. In some embodiments, a staple has a length of 16 chain atoms. In some embodiments, a staple has a length of 17 chain atoms. In some embodiments, a staple has a length of 18 chain atoms. In some embodiments, a staple has a length of 19 chain atoms. In some embodiments, a staple has a length of 20 chain atoms. In some embodiments, a staple has a length of 8-15 chain atoms. In some embodiments, a staple has 8-12 chain atoms. In some embodiments, a staple has 9-12 chain atoms. In some embodiments, a staple has 9-10 chain atoms. In some embodiments, a staple has 8-10 chain atoms. In some embodiments, length of a staple can be adjusted according to the distance of the amino acid residues it connects, for example, a longer staple may be utilized for a (i, i+7) staple than a (i, i+4) or (i, i+3) staple. In some embodiments, a (i, i+2) staple has about 5-10, 5-8, e.g., about 5, 6, 7, 8, 9 or 10 chain atoms. In some embodiments, a (i, i+2) staple has 5 chain atoms. In some embodiments, a (i, i+2) staple has 6 chain atoms. In some embodiments, a (i, i+2) staple has 7 chain atoms. In some embodiments, a (i, i+2) staple has 8 chain atoms. In some embodiments, a (i, i+2) staple has 9 chain atoms. In some embodiments, a (i, i+2) staple has 10 chain atoms. In some embodiments, a (i, i+3) staple has about 5-10, 5-8, e.g., about 5, 6, 7, 8, 9 or 10 chain atoms. In some embodiments, a (i, i+3) staple has 5 chain atoms. In some embodiments, a (i, i+3) staple has 6 chain atoms. In some embodiments, a (i, i+3) staple has 7 chain atoms. In some embodiments, a (i, i+3) staple has 8 chain atoms. In some embodiments, a (i, i+3) staple has 9 chain atoms. In some embodiments, a (i, i+3) staple has 10 chain atoms. In some embodiments, a (i, Page 62 of 884 12834799v1Attorney Docket Number: 2012675-0389 i+4) staple has about 5-12, 5-10, 7-12, 5-8, e.g., about 5, 6, 7, 8, 9, 10, 11 or 12 chain atoms. In some embodiments, a (i, i+4) staple has 5 chain atoms. In some embodiments, a (i, i+4) staple has 6 chain atoms. In some embodiments, a (i, i+4) staple has 7 chain atoms. In some embodiments, a (i, i+4) staple has 8 chain atoms. In some embodiments, a (i, i+4) staple has 9 chain atoms. In some embodiments, a (i, i+4) staple has 10 chain atoms. In some embodiments, a (i, i+4) staple has 11 chain atoms. In some embodiments, a (i, i+4) staple has 12 chain atoms. In some embodiments, a (i, i+7) staple has about 8-25, 10-25, 10-16, 12-15, e.g., about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 chain atoms. In some embodiments, a (i, i+7) staple has 8 chain atoms. In some embodiments, a (i, i+7) staple has 9 chain atoms. In some embodiments, a (i, i+7) staple has 10 chain atoms. In some embodiments, a (i, i+7) staple has 11 chain atoms. In some embodiments, a (i, i+7) staple has 12 chain atoms. In some embodiments, a (i, i+7) staple has 13 chain atoms. In some embodiments, a (i, i+7) staple has 14 chain atoms. In some embodiments, a (i, i+7) staple has 15 chain atoms. In some embodiments, a (i, i+7) staple has 16 chain atoms. In some embodiments, a (i, i+7) staple has 17 chain atoms. In some embodiments, a (i, i+7) staple has 18 chain atoms. In some embodiments, a (i, i+7) staple has 19 chain atoms. In some embodiments, a (i, i+7) staple has 20 chain atoms. In some embodiments, a (i, i+7) staple has 21 chain atoms. In some embodiments, a (i, i+7) staple has 22 chain atoms. In some embodiments, a stapled peptide comprises three or more staples, each of which is independently such a (I, i+2), (i, i+3), (i, i+4) or (i, i+7) staple. In some embodiments, a stapled peptide comprises such a (i, i+2) staple, such a (i, i+4) staple and such a (i, i+7) staple. In some embodiments, a stapled peptide comprises such a (i, i+3) staple, such a (i, i+4) staple and such a (i, i+7) staple. In some embodiments, a stapled peptide comprises such a (i, i+3) staple, such a (i, i+7) staple and such a (i, i+7) staple.

[0196] Staple lengths may be otherwise described. For example, in some embodiments, staple lengths may be described as the total number of chain atoms and non-chain ring atoms, where a non-chain ring atom is an atom of the staple which forms a ring with one or more chain atoms but is not a chain atom in that it is not within the shortest covalent connection from a first end of the staple to a second end of the staple. In some embodiments, staples formed using Monomer A (which comprises an azetidine moiety), Monomer B (which comprises a pyrrolidine moiety), and / or Monomer C (which comprises a pyrrolidine moiety), etc., may comprise one or two non-chain ring atoms.

[0197] In some embodiments, a staple has no heteroatoms in its chain. In some embodiments, a staple comprises at least one heteroatom in its chain. In some embodiments, a staple comprises at least one nitrogen atom in its chain.

[0198] In some embodiments, a staple is Ls, wherein Lsis an optionally substituted, bivalent C8-14aliphatic group wherein one or more methylene units of the aliphatic group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−. In some embodiments, a staple is Ls, wherein Lsis an optionally substituted, bivalent C9-13aliphatic group wherein one Page 63 of 884 12834799v1Attorney Docket Number: 2012675-0389 or more methylene units of the aliphatic group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−. In some embodiments, a staple is Ls, wherein Lsis an optionally substituted, bivalent C10-15aliphatic group wherein one or more methylene units of the aliphatic group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−. In some embodiments, a staple is Ls, wherein Lsis an optionally substituted, bivalent C11-14aliphatic group wherein one or more methylene units of the aliphatic group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−. In some embodiments, a staple is a (i, i+2) staple in that not including the two amino acid residues that are directly connected to the staple, there are one amino acid residue between the two amino acid residues that are directly connected to the staple. In some embodiments, a staple is a (i, i+3) staple in that not including the two amino acid residues that are directly connected to the staple, there are two amino acid residues between the two amino acid residues that are directly connected to the staple. In some embodiments, a staple is a (i, i+4) staple in that not including the two amino acid residues that are directly connected to the staple, there are three amino acid residues between the two amino acid residues that are directly connected to the staple. In some embodiments, a staple is a (i, i+7) staple in that not including the two amino acid residues that are directly connected to the staple, there are six amino acid residues between the two amino acid residues that are directly connected to the staple.

[0199] In some embodiments, for each of Ls, Ls1, Ls2, and Ls3, any replacement of methylene units, if any, is replaced with −N(R’)−, −C(O)−N(R’)−, −N(R’)C(O)O−, −C(O)O−, −S(O)2N(R’)−, or −O−. In some embodiments, for each of Ls, Ls1, Ls2, and Ls3, any replacement of methylene units, if any, is replaced with −N(R’)−, −N(R’)−C(O)−, or −N(R’)C(O)O−. In some embodiments, for each of Ls, Ls1, Ls2, and Ls3, any replacement of methylene units, if any, is replaced with −N(R’)− or −N(R’)C(O)O−. In some embodiments, for each of Ls, Ls1, Ls2, and Ls3, any replacement of methylene units, if any, is replaced with −N(R’)−. In some embodiments, for each of Ls, Ls1, Ls2, and Ls3, any replacement of methylene units, if any, is replaced with −N(R’)C(O)O−.

[0200] In some embodiments, a staple comprises a double bond. In some embodiments, a staple comprises a double bond may be formed by olefin metathesis of two olefins. In some embodiments, staples are formed by metathesis reactions, e.g., involving one or more double bonds in amino acid residues as described herein. In some embodiments, a first amino acid residue comprising an olefin (e.g., AA1−CH=CH2) and a second amino acid residue comprising an olefin (e.g., AA2−CH=CH2) are stapled (e.g., forming AA1−CH=CH−AA2, wherein AA1 and AA2 are typically linked through one or more amino acid residues). In some embodiments, an olefin, e.g., in a staple, is converted into −CHR’−CHR’−, wherein each R’ is independently as described herein. In some embodiments, R’ is R as described herein. In some Page 64 of 884 12834799v1Attorney Docket Number: 2012675-0389 embodiments, R’ is −H. In some embodiments, each R’ is −H. In some embodiments, R’ is −OR, wherein R is as described herein. In some embodiments, R’ is −OH. In some embodiments, R’ is −N(R)2wherein each R is independently as described herein. In some embodiments, R’ is −SR wherein R is as described herein. In some embodiments, R’ is R wherein R is optionally substituted aliphatic, e.g., C1-10aliphatic. In some embodiments, R’ is R wherein R is optionally substituted aliphatic, e.g., C1-10alkenyl. In some embodiments, R’ is R wherein R is optionally substituted aliphatic, e.g., C1-10 alkynyl. In some embodiments, −CHR’−CHR’− is −CH2−CH2−. In some embodiments, each of the two olefins is independently of a side chain of an amino acid residue. In some embodiments, each olefin is independently a terminal olefin. In some embodiments, each olefin is independently a mono-substituted olefin.

[0201] In some embodiments, an amino acid of formula A-I or a salt thereof is a compound having the structure of formula A-II: NH(Ra1)−La1−C(−La−CH=CH2)(Ra3)−La2−COOH, A-II or a salt thereof, wherein each variable is independently as described in the present disclosure. In some embodiments, an amino acid suitable for stapling has the structure of formula A-II or a salt thereof, wherein each variable is independently as described in the present disclosure.

[0202] In some embodiments, an amino acid of formula A-II or a salt thereof is a compound having the structure of formula A-II-b: NH(Ra1)−C(−La−CH=CH2)(Ra3)−COOH, A-II-b or a salt thereof, wherein each variable is independently as described in the present disclosure. In some embodiments, an amino acid suitable for stapling has the structure of formula A-II-b or a salt thereof, wherein each variable is independently as described in the present disclosure.

[0203] In some embodiments, an amino acid of formula A-I or a salt thereof is a compound having the structure of formula A-III: N(−La−CH=CH2)(Ra1)−La1−C(−La−CH=CH2)(Ra3)−La2−COOH, A-III or a salt thereof, wherein each variable is independently as described in the present disclosure. In some embodiments, an amino acid suitable for stapling has the structure of formula A-II or a salt thereof, wherein each variable is independently as described in the present disclosure.

[0204] In some embodiments, an amino acid of formula A-I or a salt thereof has structure of formula A- IV: NH(Ra1)−La1−C(−La−COOH)(Ra3)−La2−COOH, A-IV or a salt thereof, wherein each variable is independently as described in the present disclosure. In some Page 65 of 884 12834799v1Attorney Docket Number: 2012675-0389 embodiments, an amino acid suitable for stapling has the structure of formula A-IV or a salt thereof, wherein each variable is independently as described in the present disclosure.

[0205] In some embodiments, an amino acid has structure of formula A-V: NH(Ra1)−La1−C(−La−RSP1)(Ra3)−La2−COOH, A-V or a salt thereof, wherein each variable is independently as described in the present disclosure. In some embodiments, an amino acid suitable for stapling has the structure of formula A-V or a salt thereof, wherein each variable is independently as described in the present disclosure.

[0206] In some embodiments, an amino acid for stapling has structure of formula A-VI: NH(Ra1)−La1−C(−La−RSP1)(−La−RSP2)−La2−COOH, A-VI or a salt thereof, wherein each variable is independently as described in the present disclosure. In some embodiments, an amino acid suitable for stapling has the structure of formula A-VI or a salt thereof, wherein each variable is independently as described in the present disclosure.

[0207] As used herein, each of RSP1and RSP2independently comprises a reactive group. In some embodiments, each of RSP1and RSP2is independently a reactive group. In some embodiments, a reactive group is optionally substituted −CH=CH2. In some embodiments, a reactive group is −CH=CH2. In some embodiments, a reactive group is an amino group, e.g., −NHR, wherein R is as described herein. In some embodiments, a reactive group is an acid group. In some embodiments, a reactive group is −COOH or an activated form thereof. In some embodiments, a reactive group is for a cycloaddition reaction (e.g., [3+2], [4+2], etc.), e.g., an alkene, an alkyne, a diene, a 1,3-dipole (e.g., −N3), etc. In some embodiments, a reactive group is optionally substituted −C≡CH. In some embodiments, a reactive group is −C≡CH. In some embodiments, a reactive group is −N3.

[0208] In some embodiments, RSP1or RSP2of a first amino acid residue and RSP1or RSP2of a second amino acid residue can react with each other so that the two amino acid residues are connected with a staple. In some embodiments, a reactive is olefin metathesis between two olefin, e.g., two −CH=CH2. In some embodiments, a reaction is amidation and one reactive group is an amino group, e.g., −NHR wherein R is as described herein (e.g., in some embodiments, R is −H; in some embodiments, R is optionally substituted C1-6aliphatic), and the other is an acid group (e.g., −COOH) or an activated form thereof. In some embodiments, a reaction is a cycloaddition reaction, e.g., [4+2], [3+2], etc. In some embodiments, a first and a second reactive groups are two reactive groups suitable for a cycloaddition reaction. In some embodiments, a reaction is a click reaction. In some embodiments, one reaction group is or comprises −N3, and the other is or comprises an alkyne, e.g., a terminal alkyne or a activated / strained alkyne. In some embodiments, the other is or comprises −C≡CH.

[0209] In some embodiments, RSP1or RSP2of a first amino acid residue and RSP1or RSP2of a second amino acid residue can react with a reagent so that the two are connected to form a staple. In some Page 66 of 884 12834799v1Attorney Docket Number: 2012675-0389 embodiments, a reagent comprises two reactive groups, one of which reacts with RSP1or RSP2of a first amino acid residue, and the other reacts with RSP1or RSP2of a first amino acid residue. In some embodiments, RSP1or RSP2of both amino acid residues are the same or the same type, e.g., both are amino groups, and the two reactive groups of a linking reagent are also the same, e.g., both are acid groups such as −COOH or activated form thereof. In some embodiments, RSP1or RSP2of both amino acid residues are both acid groups, e.g., −COOH or activated form thereof, and both reactive groups of a linking agent are amino groups. In some embodiments, RSP1or RSP2of both amino acid residues are both nucleophilic groups, e.g., −SH, and both reactive groups of a linking reagent are electrophilic (e.g., carbon attached to leaving groups such as −Br, −I, etc.).

[0210] In some embodiments, RSP1and RSP2are the same. In some embodiments, RSP1and RSP2are different. In some embodiments, RSP1is or comprises −CH=CH2. In some embodiments, RSP1is or comprises −COOH. In some embodiments, RSP1is or comprises an amino group. In some embodiments, RSP1is or comprises −NHR. In some embodiments, R is hydrogen or optionally substituted C1-6aliphatic. In some embodiments, RSP1is or comprises −NH2. In some embodiments, RSP1is or comprises −N3. In some embodiments, RSP2is or comprises −CH=CH2. In some embodiments, RSP2is or comprises −COOH. In some embodiments, RSP2is or comprises an amino group. In some embodiments, RSP2is or comprises −NHR. In some embodiments, R is hydrogen or optionally substituted C1-6aliphatic. In some embodiments, RSP2is or comprises −NH2. In some embodiments, RSP2is or comprises −N3.

[0211] In some embodiments, each amino acid residue of a pair of amino acid residues is independently a residue of an amino acid of formula A-II or A-III or a salt thereof. In some embodiments, such a pair of amino acid residues is stapled, e.g., through olefin metathesis. In some embodiments, a staple has the structure of −La−CH=CH−La−, wherein each variable is independently as described herein. In some embodiments, olefin in a staple is reduced. In some embodiments, In some embodiments, a staple has the structure of −La−CH2−CH2−La−, wherein each variable is independently as described herein. In some embodiments, one Lais Ls1as described herein, and one Lais Ls3as described herein.

[0212] In some embodiments, two amino acid residues, e.g., of amino acids independently of formula A- I or a salt of, connected by a staple have the structure of −N(Ra1)−La1−C(−Ls−RAA)(Ra3)−La2−CO−, wherein each variable is independently as described herein, and RAAis an amino acid residue. In some embodiments, two amino acid residues, e.g., of amino acids independently of formula A-I or a salt of, connected by a staple have the structure of −N(−Ls−RAA)−La1−C(Ra2)(Ra3)−La2−CO−, wherein each variable is independently as described herein, and RAAis an amino acid residue. In some embodiments, two amino acid residues, e.g., of amino acids independently of formula A-I or a salt of, connected by a staple have the structure of Ra1−N(−Ls−RAA)−La1−C(Ra2)(Ra3)−La2−CO−, wherein each variable is independently as described herein, and RAAis an amino acid residue. In some embodiments, three amino acid residues, e.g., of amino acids independently of formula A-I or a salt of, connected by two staples have the structure of Ra1−N(−Ls−RAA)−La1−C(−Ls−RAA)(Ra3)−La2−CO−, wherein each variable is independently as described Page 67 of 884 12834799v1Attorney Docket Number: 2012675-0389 herein, and RAAis an amino acid residue. In some embodiments, three amino acid residues, e.g., of amino acids independently of formula A-I or a salt of, connected by two staples have the structure of −N(−Ls−RAA)−La1−C(−Ls−RAA)(Ra3)−La2−CO−, wherein each variable is independently as described herein, and RAAis an amino acid residue. In some embodiments, three amino acid residues, e.g., of amino acids independently of formula A-I or a salt of, connected by two staples (e.g., X4stapled with both X1and X14) have the structure of −N(Ra1)−La1−C(−Ls−RAA)(−Ls−RAA)−La2−CO−, wherein each variable is independently as described herein, and RAAis an amino acid residue. In some embodiments, each RAAis independently a residue of an amino acid of formula A-I, A-II, A-III, A-IV, A-V, A-VI, etc. or a salt thereof. In some embodiments, RAAis −C(Ra3)[−La1−N(Ra1)−](−La2−CO−), wherein each variable is independently as described herein. In some embodiments, RAAis −C(Ra3)[−N(Ra1)−](−CO−), wherein each variable is independently as described herein. In some embodiments, each RAAis independently −N(−)[−La1−C(Ra2)(Ra3)−La2−CO−], wherein each variable is independently as described herein, wherein −C(−)(Ra3)− is bonded to a staple. In some embodiments, each RAAis independently −N(−)[−C(Ra2)(Ra3)−CO−], wherein each variable is independently as described herein, wherein −C(−)(Ra3)− is bonded to a staple. In some embodiments, each RAAis independently Ra1−N(−)[−La1−C(Ra2)(Ra3)−La2−CO−], wherein each variable is independently as described herein, wherein −C(−)(Ra3)− is bonded to a staple. In some embodiments, each RAAis independently Ra1−N(−)[−C(Ra2)(Ra3)−CO−], wherein each variable is independently as described herein, wherein −C(−)(Ra3)− is bonded to a staple.

[0213] Various staples, e.g., Ls, are as described herein. In some embodiments, Lsis −Ls1−Ls2−Ls3− as described herein. In some embodiments, Ls1is Laas described herein. In some embodiments, Ls3is Laas described herein. In some embodiments, Ls1is Laof a first of two stapled amino acid residues. In some embodiments, Ls2is Laof a second of two stapled amino acid residues. In some embodiments, Ls2is or comprises a double bond. In some embodiments, Ls2is or comprises −CH=CH−. In some embodiments, Ls2is or comprises optionally substituted −CH2−CH2−. In some embodiments, Ls2is or comprises −CH2−CH2−. In some embodiments, Ls2is or comprises −C(O)N(R’)− (e.g., a staple formed by two amino acid residues one of which has a RSP1group that is or comprises an amino group and the other of which has a RSP2group that is or comprises −COOH). In some embodiments, Ls2is or comprises −C(O)NH−. In some embodiments, each of Ls1and Ls3is independently optionally substituted linear or branched C1-10hydrocarbon chain. In some embodiments, each of Ls1and Ls3is independently −(CH2)n−, wherein n is 1-10. In some embodiments, Ls1is −CH2−. In some embodiments, Ls3is −(CH2)3−.

[0214] In some embodiments, Lsis −CH2−CH=CH−(CH2)3−. In some embodiments, Lsis −(CH2)6−.

[0215] In some embodiments, Lsis −(CH2)2−C(O)NH−(CH2)4−.

[0216] In some embodiments, Lsis bonded to two backbone carbon atoms. In some embodiments, Lsis bonded to two alpha carbon atoms of two stapled amino acid residues. In some embodiments, Lsis bonded to a backbone nitrogen atom and a backbone carbon atom (e.g., an alpha carbon). Page 68 of 884 12834799v1Attorney Docket Number: 2012675-0389

[0217] In some embodiments, Lacomprises at least one −N(R’)− wherein R’ is independently as described in the present disclosure. In some embodiments, Lacomprises −Lam1−N(R’)− wherein R’ is independently as described in the present disclosure, and Lam1is as described herein. In some embodiments, Lais or comprises −Lam1−N(R’)−Lam2−, wherein each of Lam1, R’, and Lam2is independently as described herein. In some embodiments, R’ is optionally substituted C1-6aliphatic. In some embodiments, R’ is methyl. In some embodiments, R’ is taken together with Ra3to form an optionally substituted ring as described herein. In some embodiments, a formed ring is a 3-10 membered monocyclic saturated ring as described herein. In some embodiments, a formed ring has no additional heteroatom ring atom in addition to the nitrogen of −N(R’)−. In some embodiments, a formed ring is 3-membered. In some embodiments, a formed ring is 4-membered. In some embodiments, a formed ring is 5-membered. In some embodiments, a formed ring is 6-membered.

[0218] In some embodiments, Lacomprises at least one −C(R’)2− wherein each R’ is independently as described in the present disclosure. In some embodiments, Lacomprises −Lam1−C(R’)2− wherein R’ is independently as described in the present disclosure, and Lam1is as described herein. In some embodiments, Lais or comprises −Lam1−C(R’)2−Lam2−, wherein each of Lam1, R’, and Lam2is independently as described herein. In some embodiments, R’ is −H. In some embodiments, −C(R’)2− is optionally substituted −CH2−. In some embodiments, −C(R’)2− is −CH2−. In some embodiments, one R’ is taken together with Ra3to form an optionally substituted ring as described herein. In some embodiments, a formed ring is a 3-10 membered monocyclic saturated ring as described herein. In some embodiments, a formed ring has no additional heteroatom ring atom in addition to the nitrogen of −N(R’)−. In some embodiments, a formed ring is 3- membered. In some embodiments, a formed ring is 4-membered. In some embodiments, a formed ring is 5- membered. In some embodiments, a formed ring is 6-membered.

[0219] As described herein, each of Lam1and Lam2is independently Lamas described herein. As described herein, Lamis a covalent bond, or an optionally substituted, bivalent C1-C10aliphatic group wherein one or more methylene units of the aliphatic group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−. In some embodiments, Lamis a covalent bond. In some embodiments, Lamis an optionally substituted bivalent C1-C10aliphatic group. In some embodiments, Lamis an optionally substituted bivalent linear C1-C10aliphatic group. In some embodiments, Lamis optionally substituted C1-10alkylene. In some embodiments, Lamis C1-10alkylene. In some embodiments, Lamis optionally substituted linear C1-10alkylene. In some embodiments, Lamis optionally substituted −CH2−. In some embodiments, Lamis −CH2−.

[0220] In some embodiments, Lam1is a covalent bond. In some embodiments, Lam1is an optionally substituted bivalent C1-C10aliphatic group. In some embodiments, Lam1is an optionally substituted bivalent linear C1-C10aliphatic group. In some embodiments, Lam1is optionally substituted C1-10alkylene. In some embodiments, Lam1is C1-10alkylene. In some embodiments, Lam1is optionally substituted linear C1-10Page 69 of 884 12834799v1Attorney Docket Number: 2012675-0389 alkylene. In some embodiments, Lam1is optionally substituted −CH2−. In some embodiments, Lam1is −CH2−. In some embodiments, Lam1is bonded to a backbone atom. In some embodiments, Lam1is bonded to an alpha- carbon of an amino acid.

[0221] In some embodiments, Lam2is a covalent bond. In some embodiments, Lam2is an optionally substituted bivalent C1-C10aliphatic group. In some embodiments, Lam2is an optionally substituted bivalent linear C1-C10 aliphatic group. In some embodiments, Lam2is optionally substituted C1-10 alkylene. In some embodiments, Lam2is C1-10alkylene. In some embodiments, Lam2is optionally substituted linear C1-10alkylene. In some embodiments, Lam2is optionally substituted −CH2−. In some embodiments, Lam2is −CH2−. In some embodiments, Lam2is or comprises −C(O)−. In some embodiments, −C(O)− is bonded to a nitrogen atom. In some embodiments, Lam2is or comprises −S(O)2−. In some embodiments, −S(O)2− is bonded to a nitrogen atom. In some embodiments, Lam2is or comprises −O−. In some embodiments, Lam2is or comprises −C(O)−O−. In some embodiments, −C(O)−O− is bonded to a nitrogen atom. In some embodiments, Lam2is bonded to a nitrogen atom, and it comprises a −C(O)− group which is bonded to the nitrogen atom. In some embodiments, Lam2is bonded to a nitrogen atom, and it comprises a −C(O)−O− group which is bonded to the nitrogen atom. In some embodiments, Lam2is or comprises −C(O)−O−CH2−, wherein the −CH2− is optionally substituted. In some embodiments, Lam2is −C(O)−O−CH2−.

[0222] In some embodiments, Lais Ls1as described herein. In some embodiments, Lais Ls2as described herein.

[0223] In some embodiments, Ra3is −La−CH=CH2, wherein Lais independently as described herein. In some embodiments, each of Ra2and Ra3independently comprises a double bond, e.g., a terminal olefin which can be optionally and independently stapled with another residue comprising an olefin. In some embodiments, each of Ra2and Ra3are independently −La−CH=CH2. In some embodiments, an amino acid are stapled with two amino acid residues independently through Ra2and Ra3. In some embodiments, such an amino acid is B5. In some embodiments, it is B3. In some embodiments, it is B4. In some embodiments, it is B6.

[0224] In some embodiments, an amino acid is selected from Tables A-I, A-II, A-III and A-IV (may be presented as Fmoc-protected). As appreciated by those skilled in the art, among other things, when incorporated into peptides, Fmoc-protected amino groups and carboxyl groups may independently form amide connections with other amino acid residues (or N- or C-terminus capping groups, or exist as N- or C- terminus amino or carboxyl groups). Olefins, including those in Alloc groups, may be utilized to form staples through olefin metathesis. Staples comprising olefins may be further modified, e.g., through hydrogenation to convert olefin double bonds into single bonds, and / or through CO2extrusion to convert carbamate moieties (e.g., −O−(CO)−N(R’)−) into amine moieties (e.g., −N(R’)−). In some embodiments, an agent is or comprises a stapled peptide (e.g., a stapled peptide described according to Table E1) or a salt thereof, in which stapled peptide each double bond is converted into a single bond. In some embodiments, a conversion is achieved through hydrogenation which adds a −H to each olefin carbon atom. In some embodiments, an Page 70 of 884 12834799v1Attorney Docket Number: 2012675-0389 olefin double bond is replaced with −CHR’−CHR’−, wherein each R’ is independently as described herein. In some embodiments, R’ is R as described herein. In some embodiments, R’ is −H. In some embodiments, each R’ is −H. In some embodiments, R’ is −OR, wherein R is as described herein. In some embodiments, R’ is −OH. In some embodiments, R’ is −N(R)2wherein each R is independently as described herein. In some embodiments, R’ is −SR wherein R is as described herein. In some embodiments, R’ is R wherein R isoptionally substituted aliphatic, e.g., C1-10 aliphatic. In some embodiments, R’ is R wherein R is optionallysubstituted aliphatic, e.g., C1-10alkenyl. In some embodiments, R’ is R wherein R is optionally substituted aliphatic, e.g., C1-10alkynyl. In some embodiments, −CHR’−CHR’− is −CH2−CH2−. Table A-I. Exemplary amino acids (Fmoc-Protected). Monomer A (MA) Monomer B (MB) Monomer C (MC) Alloc AllocN AllocN. . Monomer D (MD) Monomer E (ME) Monomer F (MF)Table A-III. Exemplary amino acids (Fmoc-Protected). S3 R3 S412834799v1Attorney Docket Number: 2012675-0389 ocPage 72 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O O O O HO N O HO N O OHmino acid is an L-amino acid. In some embodiments, an amino acid is a D-amino acid. In some embodiments, the alpha-carbon of an amino acid is achiral. In some embodiments, an amino acid is a beta-amino acid. In some embodiments, an amino acid is a gamma-amino acid.

[0226] In some embodiments, a provided amino acid sequence contains two or more amino acid residues whose side chains are linked together to form one or more staples. In some embodiments, a provided amino acid sequence contains two or more amino acid residues, each of which independently has a side chain comprising an olefin. In some embodiments, a provided amino acid sequence contains two or more amino acid residues, each of which independently has a side chain comprising a terminal olefin. In some embodiments, a provided amino acid sequence contains two and no more than two amino acid residues, each of which independently has a side chain comprising an olefin. In some embodiments, a provided amino acid sequence contains two and no more than two amino acid residues, each of which independently has a side chain comprising a terminal olefin. In some embodiments, a provided amino acid sequence comprises at least one residue of an amino acid that comprises an olefin and a nitrogen atom other than the nitrogen atom of its amino group. In some embodiments, a provided amino acid sequence comprises at least one residue of an amino acid that comprises a terminal olefin and a nitrogen atom other than the nitrogen atom of its amino group. In some embodiments, a provided amino acid sequence comprises at least one residue of an amino acid that has a side chain than comprises a terminal olefin and a nitrogen atom. In some embodiments, a provided amino acid sequence comprises at least one residue of an amino acid of formula A-I, wherein Ra2comprising an olefin and a −N(R’)− moiety, wherein R’ is as described in the present disclosure (including, in some embodiments, optionally taken together with Ra3and their intervening atoms to form an optionally substituted ring as described in the present disclosure). In some embodiments, Ra2comprising a terminal olefin and a −N(R’)− moiety wherein R’ is as described in the present disclosure. In some embodiments, a provided amino acid sequence comprises at least one residue of an amino acid selected from Table A-I. In some embodiments, a provided amino acid sequence comprises at least one residue of an amino acid selected from Table A-II. In some embodiments, a provided amino acid sequence comprises at least one residue of an amino acid selected from Table A-III. In some embodiments, two olefins from two side chains are linked Page 73 of 884 12834799v1Attorney Docket Number: 2012675-0389 together through olefin metathesis to form a staple. In some embodiments, a staple is preferably formed by side chains of amino acid residues that are not at the corresponding positions of a target of interest. In some embodiments, a formed staple does not disrupt interaction between the peptide and a target of interest.

[0227] In some embodiments, a provided staple is a hydrocarbon staple. In some embodiments, a hydrocarbon staple comprises no chain heteroatoms wherein a chain of a staple is the shortest covalent connection within the staple from one end of the staple to the other end of the staple.

[0228] In some embodiments, an olefin in a staple is a Z-olefin. In some embodiments, an olefin in a staple in an E-olefin. In some embodiments, a provided composition comprises stapled peptides comprising a staple that contains a Z-olefin and stapled peptides comprising a staple that contains an E-olefin. In some embodiments, a provided composition comprises stapled peptides comprising a staple that contains a Z- olefin. In some embodiments, a provided composition comprises stapled peptides comprising a staple that contains an E-olefin. In some embodiments, otherwise identical stapled peptides that differ only in the E / Z configuration of staple olefin demonstrate different properties and / or activities as demonstrated herein. In some embodiments, stapled peptides with E-olefin in a staple may provide certain desirable properties and / or activities given the context. In some embodiments, stapled peptides with Z-olefin in a staple may provide certain desirable properties and / or activities given the context.

[0229] In some embodiments, the present disclosure provides compositions comprising stapled peptides. In some embodiments, a composition comprises one and only one stereoisomer of a stapled peptide (e.g., E or Z isomer, and / or a single diastereomer / enantiomer with respect to a chiral center, etc.). In some embodiments, a composition comprises two or more stereoisomers (e.g., both E and Z isomers of one or more double bonds, and / or one or more diastereomers / enantiomers with respect to a chiral center, etc.). In some embodiments, a composition corresponds to a single peak in a chromatographic separation, e.g., HPLC. In some embodiments, a peak comprises one and only one stereoisomers. In some embodiments, a peak comprises two or more stereoisomers.

[0230] In some embodiments, two staples may be bonded to the same atom of the peptide backbone, forming a stitched peptide.

[0231] In some embodiments, a staple is pro-lock wherein one end of the staple is bonded to the alpha- carbon of a proline residue.

[0232] In some embodiments, a staple is a staple illustrated below in Tables S-1, S-2, S-3, S-4 and S-5 (with exemplary peptide backbone illustrated for clarity (can be applied to other peptide backbone), each X independently being an amino acid residue). In some embodiments, a staple is a staple in Table S-6 (with amino acid residues bonded to staples illustrated). In some embodiments, the olefin is Z. In some embodiments, the olefin is E. In some embodiments, an (i, i+3) staple is selected from Table S-1. In some embodiments, an (i, i+3) staple is selected from Table S-2. Those skilled in the art reading the present disclosure will appreciate that when staples in Table S-1 and Table S-2 are utilized for (i, i+3), “X3” in those tables would be “X2” (i.e., two amino acid residues instead of three amino acid residues). In some Page 74 of 884 12834799v1Attorney Docket Number: 2012675-0389 embodiments, an (i, i+4) staple is selected from Table S-1. In some embodiments, an (i, i+4) staple is selected from Table S-2. In some embodiments, an (i, i+7) staple is selected from Table S-3. In some embodiments, an (i, i+7) staple is selected from Table S-4. Table S-1. Exemplary staples. O O NO N O,Page 75 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O ON N O,,Page 76 of 884 12834799v1Attorney Docket Number: 2012675-0389 O OO ON,,Page 77 of 884 12834799v1Attorney Docket Number: 2012675-0389 N N ,Page 78 of 884 12834799v1Attorney Docket Number: 2012675-0389 N N ,,, ,Page 79 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O NOON,,,,,,,Page 80 of 884 12834799v1Attorney Docket Number: 2012675-0389 NO N O, ,,,, ,,Page 81 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O O N O N ,,,,,,,Page 82 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O O O NOO NN OO N , , , , , , ,Page 83 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O O O NOO NN OO N , , , , , , ,Page 84 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O O O NOO NN OO N , , , , , ,Page 85 of 884 12834799v1Attorney Docket Number: 2012675-0389 N N ,,, ,.

[0233] Certain useful staples are described in, e.g., WO 2019 / 051327, WO 2022 / 020652, etc. and are incorporated herein by reference.

[0234] In some embodiments, a staple may be one of the following, connecting the amino acids at the indicated position: Table S-5. Certain amino acids and staples. Page 86 of 884 12834799v1Attorney Docket Number: 2012675-0389 staplePage 87 of 884 12834799v1Attorney Docket Number: 2012675-0389 StaplePage 88 of 884 12834799v1Attorney Docket Number: 2012675-0389 StaplePage 89 of 884 12834799v1Attorney Docket Number: 2012675-0389 StaplePage 90 of 884 12834799v1Attorney Docket Number: 2012675-0389 sta lePage 91 of 884 12834799v1Attorney Docket Number: 2012675-0389 StaplePage 92 of 884 12834799v1Attorney Docket Number: 2012675-0389 staplePage 93 of 884 12834799v1Attorney Docket Number: 2012675-0389 StaplePage 94 of 884 12834799v1Attorney Docket Number: 2012675-0389 StaplePage 95 of 884 12834799v1Attorney Docket Number: 2012675-0389 staplePage 96 of 884 12834799v1Attorney Docket Number: 2012675-0389 staplePage 97 of 884 12834799v1Attorney Docket Number: 2012675-0389 staplePage 98 of 884 12834799v1Attorney Docket Number: 2012675-0389 sta lePage 99 of 884 12834799v1Attorney Docket Number: 2012675-0389 sta le [0 two staples) from Table S-6. In Tae 6, t e amno ac res ues can e t er e rom N to C or C to N. n some embodiments, it is N to C. In some embodiments, it is C to N. In some embodiments, a double bond is E. In some embodiments, a double bond is Z. In some embodiments, a staple is a (i, i+2) staple. In some embodiments, a staple is a (i, i+3) staple. In some embodiments, a staple is a (i, i+4) staple. In some embodiments, a staple is a (i, i+7) staple. In some embodiments, each double is independently E or Z when a structure comprises more than one double bond. In some embodiments, each staple is independently a (i, i+2) or a (i, i+3) or a (i, i+4) staple or a (i, i+7) staple. In some embodiments, each staple is independently a (i, i+2) or a (i, i+4) staple or a (i, i+7) staple. In Page 100 of 884 12834799v1Attorney Docket Number: 2012675-0389 some embodiments, each staple is independently a (i, i+3) or a (i, i+4) staple or a (i, i+7) staple. In some embodiments, each staple is independently a (i, i+4) staple or a (i, i+7) staple in a structure comprising two staples. In some embodiments, one staple is a (i, i+4) staple and the other is a (i, i+7) staple. In some embodiments, one staple is a (i, i+3) staple, one staple is a (i, i+4) staple and one staple is a (i, i+7) staple. In some embodiments, one staple is a (i, i+2) staple, one staple is a (i, i+4) staple and one staple is a (i, i+7) staple. In some embodiments, a PL3 residue is bonded to a (i, i+3) staple. In some embodiments, a PL3 residue is bonded to a (i, i+4) staple. In some embodiments, staples (e.g., those in Table 6) are formed by metathesis of double bonds in side chains of amino acid residues, e.g., RdN and S7, R8 and PyrS, R5 and SeN, R6 and SeN, ReN and S5, ReN and S6, R7 and PyrS, Az and S7, R8 and SgN, Az and S8, R4 and SeN, R5 and SdN, R7 and Az, R8 and Az, RdN and S4, RgN and S8, RgN and S7, R8 and S5, PL3 and B5 and the same B5 and S8, PL3 and B5 and the same B5 and SeN, PL3 and B5 and the same B5 and SdN, PL3 and B5 and the same B5 and S7, PL3 and B5 and the same B5 and PyrS2, PL3 and B5 and the same B5 and PyrS3, R5 and PyrS2, PL3 and B5 and the same B5 and PyrS1, PL3 and B5 and the same B5 and S10, PL3 and B5 and the same B5 and PyrR2, PL3 and B5 and the same B5 and PyrS, PL3 and B5 and the same B5 and Az, PL3 and B5 and the same B5 and SeNc5, HypEs5 and B5 and the same B5 and PyrS2, HypEs4 and B5 and the same B5 and PyrS2, ProSAm3 and B5 and the same B5 and PyrS2, ProAm5 and B5 and the same B5 and PyrS2, ProAm6 and B5 and the same B5 and PyrS2, BzAm3Oallyl and B5 and the same B5 and PyrS2, HypBzEs3OAllyl and B5 and the same B5 and PyrS2, ProBzAm3OAllyl and B5 and the same B5 and PyrS2, PAc3OAllyl and B5 and the same B5 and PyrS2, ProPAc3OAllyl and B5 and the same B5 and PyrS2, HypPAc3OAllyl and B5 and the same B5 and PyrS2, Bn3OAllyl and B5 and the same B5 and PyrS2, R3 and B5 and the same B5 and PyrS2, R5 and B5 and the same B5 and PyrS2, [BzAm2Allyl]MePro and B5 and the same B5 and PyrS2, PL3 and B5 and the same B5 and SPip1, PL3 and B5 and the same B5 and SPip2, PL3 and B5 and the same B5 and SPip3, PL3 and B5 and the same B5 and Az2, PL3 and B5 and the same B5 and Az3, PL3 and S5, R5 and S5, PL3 and B4 and the same B4 and PyrS1, PL3 and B4 and the same B4 and PyrS2, PL3 and B4 and the same B4 and PyrS3, PL3 and S6, PL3 and S4, PL3 and S3, R6 and PyrS2, R4 and PyrS2, R3 and PyrS2, PL3 and B3 and the same B3 and PyrS2, PL3 and B3 and the same B3 and PyrS3, PL3 and B3 and the same B3 and PyrS4, PL3 and B6 and the same B6 and PyrS, PL3 and B6 and the same B6 and PyrS1, PL3 and B6 and the same B6 and PyrS2. Table S-6. Certain staples (including amino acid residues bonded to staples). O ,Page 101 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O N N O O ,Page 102 of 884 12834799v1Attorney Docket Number: 2012675-0389 O N O ,g 12834799v1Attorney Docket Number: 2012675-0389 O O O N N O ,Page 104 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O O N O N , ,Page 105 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O N O N , ,Page 106 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O O N ,Page 107 of 884 12834799v1Attorney Docket Number: 2012675-0389 O N (S) O O ,Page 108 of 884 12834799v1Attorney Docket Number: 2012675-0389 O N (S)OO NH ,12834799v1Attorney Docket Number: 2012675-0389 O N O O , ,Page 110 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O N O O N ,Page 111 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O N O ,Page 112 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O O N O N ,

[0236] In some embodiments, the double bond in a (i, i+3) staple is Z. In some embodiments, the double bond in a (i, i+4) staple is Z. In some embodiments, the double bond in a (i, i+7) staple is Z. In some embodiments, the double bond in a (i, i+3) staple is E. In some embodiments, the double bond in a (i, i+4) staple is E. In some embodiments, the double bond in a (i, i+7) staple is E.

[0237] In some embodiments, a staple comprises −S−. In some embodiments, stapling technologies comprise utilization of one or more, e.g., two or more, sulfur-containing moieties. In some embodiments, a stapled peptide comprises cysteine stapling. In some embodiments, two cysteine residues are stapled wherein Page 113 of 884 12834799v1Attorney Docket Number: 2012675-0389 the −S− moieties of the two cysteine residues are connected optionally through a linker. In some embodiments, a stapled peptide comprises one and no more than one staples from cysteine stapling. In some embodiments, a stapled peptide comprises one and no more than one staples having the structure of O O S S SSS S N N meS S . In some embodiments, a stapled peptide comprises one and no more thanS Sone staples having the structure of . In some embodiments, a stapled peptideO O S S comprises one and no more than one staples having the structu . In some embodiments, a stapled peptide comprises no staples havO O S S SSS S meS S the gthe structure .

[0238] isclosure provides useful technologies relating to cysteine stapling. Among other things, the present disclosure appreciates that peptides amenable to cysteine stapling and / or comprising one or more cysteine staples, can be produced and / or assessed in a biological system. The present disclosure further appreciates that certain such systems permit development, production, and / or assessment of cysteine stapled peptides having a range of different structures (e.g., different amino acid sequences), and in fact can provide a user with complete control over selection and implementation of amino acid sequences to be incorporated into stapled peptides. Page 114 of 884 12834799v1Attorney Docket Number: 2012675-0389

[0239] Cysteine stapling, as described herein, involves linking one cysteine residue to another cysteine residue, where the resulting bond is not through the peptide backbone between the linked cysteine residues.

[0240] In some embodiments, a stapled peptide as described herein comprises a staple which staple is Ls, wherein: Lsis −Ls1−S−Ls2−S−Ls3−; Ls1and Ls3are each independently L; Ls2is L and comprises at least one −C(O)−; and each L is independently a covalent bond, or an optionally substituted, bivalent C1-C25aliphatic group wherein one or more methylene units of the aliphatic group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−; each −Cy− is independently an optionally substituted bivalent group selected from a C3-20cycloaliphatic ring, a C6-20aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; each R’ is independently −R, −C(O)R, −CO2R, or −SO2R; each R is independently −H, or an optionally substituted group selected from C1-30aliphatic, C1-30heteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, C6-30aryl, C6-30arylaliphatic, C6-30arylheteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or two R groups are optionally and independently taken together to form a covalent bond; or two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0241] In some embodiments, L is independently a bivalent C1-C25aliphatic group. In some embodiments, L is independently a bivalent C1-C20aliphatic group. In some embodiments, L is independently a bivalent C1-C10aliphatic group. In some embodiments, L is independently a bivalent C1-C5aliphatic group. In some embodiments, L is independently a bivalent C1aliphatic group. In some embodiments, L is −CH2. Page 115 of 884 12834799v1Attorney Docket Number: 2012675-0389

[0242] In some embodiments, Ls1is −CH2−. In some embodiments, Ls3is −CH2−. In some embodiments, Ls1and Ls3are both −CH2−. In some embodiments, Lsis −CH2−S−Ls2−S−CH2−.

[0243] In some embodiments, Ls2comprises −C(R’)2−L’−C(R’)2−, wherein L’ is described in the present disclosure. In some embodiments, Ls2is −Lx1−C(O)Q−L’−QC(O)−Lx1−, wherein each variable is independently as described in the present disclosure. In some embodiments, Ls2is −CH2C(O)Q−L’−QC(O)CH2−, wherein each −CH2− is independently and optionally substituted. In some embodiments, Ls2is −CH2C(O)Q−L’−QC(O)CH2−.

[0244] In some embodiments, Ls2In some embodiments, Ls2is L and comprises at least one −C(O)−. In some embodiments, Ls2is L and comprises at least two −C(O)−. In some embodiments, Ls2is L and comprises at least one −C(O)Q−, wherein Q is selected from the group consisting of: a covalent bond, −N(R’)−, −O−, and –S–. In some embodiments, Ls2is L and comprises at least one −C(O)Q−, wherein Q is selected between −N(R’)− and −O−. In some embodiments, Ls2is L and comprises at least two −C(O)Q−, wherein Q is selected from the group consisting of: −N(R’)−, −O−, and –S–. In some embodiments, Ls2is L and comprises at least two −C(O)Q−, wherein Q is selected between −N(R’)− and −O−. In some embodiments, Ls2is L and comprises at least one −C(O)N(R’)−. In some embodiments, Ls2is L and comprises at least two −C(O)N(R’)−. In some embodiments, Ls2is L and comprises at least one −C(O)O−. In some embodiments, Ls2is L and comprises at least two −C(O)O−.

[0245] In some embodiments, Ls2comprises −Q−L’−Q−, wherein Q is independently selected from the group consisting of: −N(R’)−, −O−, and −S, wherein L’ is described in the present disclosure.

[0246] In some embodiments, Ls2comprises −Q−L’−Q−, wherein Q is independently selected between −N(R’)− and −O−, wherein L’ is described in the present disclosure. In some embodiments, Ls2comprises – C(O)Q−L’−QC(O)−, wherein Q is independently selected from the group consisting of: −N(R’)−, −O−, and −S, wherein L’ is described in the present disclosure. In some embodiments, Ls2comprises – C(O)Q−L’−QC(O)−, wherein Q is independently selected between −N(R’)− and −O, wherein L’ is described in the present disclosure. In some embodiments, Ls2comprises –C(R’)2C(O)Q−L’−QC(O)C(R’)2−, wherein Q is independently selected from the group consisting of: −N(R’)−, −O−, and −S, wherein L’ is described in the present disclosure. In some embodiments, Ls2comprises –C(R’)2C(O)Q−L’−QC(O)C(R’)2−, wherein Q is independently selected between −N(R’)− and −O, wherein L’ is described in the present disclosure.

[0247] In some embodiments, Ls2comprises −N(R’)−L’−N(R’)−, wherein L’ is described in the present disclosure. In some embodiments, Ls2comprises −C(O)N(R’)−L’−N(R’)C(O)−, wherein L’ is described in the present disclosure. In some embodiments, Ls2is −C(R’)2C(O)N(R’)−L’−N(R’)C(O)C(R’)2−, wherein L’ is described in the present disclosure.

[0248] In some embodiments, Ls2comprises −O(R’)−L’−O(R’)−, wherein L’ is described in the present disclosure. In some embodiments, Ls2comprises −C(O)O−L’−OC(O)−, wherein L’ is described in the present disclosure. In some embodiments, Ls2is −C(R’)2C(O)O−L’−OC(O)C(R’)2−, wherein L’ is described in the present disclosure. Page 116 of 884 12834799v1Attorney Docket Number: 2012675-0389

[0249] In some embodiments, R’ is an optionally substituted C1-30aliphatic. In some embodiments, R’ is an optionally substituted C1-15aliphatic. In some embodiments, R’ is an optionally substituted C1-10aliphatic. In some embodiments, R’ is an optionally substituted C1-5aliphatic. In some embodiments, R’ is hydrogen.

[0250] In some embodiments, L’ is optionally substituted bivalent C1-C19aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C15aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C10 aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C9 aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C8aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C7aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C6aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C5aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C3aliphatic. In some embodiments, L’ is optionally substituted bivalent C1-C2aliphatic. In some embodiments, L’ is optionally substituted bivalent C1aliphatic. In some embodiments, L’ is −CH2−. In some embodiments, L’ is −(CH2)2−. In some embodiments, L’ is −(CH2)3−. In some embodiments, L’ is −(CH2)4−. In some embodiments, L’ is −(CH2)5−. In some embodiments, L’ is −(CH2)6−. In some embodiments, L’ is −(CH2)7−. In some embodiments, L’ is −(CH2)8−.

[0251] In some embodiments, L’ is optionally substituted bivalent C6-20aryl ring. In some embodiments, L’ is optionally substituted bivalent C6-14aryl ring. In some embodiments, L’ is optionally substituted bivalent C6-10aryl ring. In some embodiments, L’ is optionally substituted bivalent C6aryl ring. In some embodiments, L’ is bivalent C6aryl substituted with at least one halogen. In some embodiments, L’ is bivalent C6aryl substituted with at least two halogen. In some embodiments, L’ is bivalent C6aryl substituted with at least three halogen. In some embodiments, L’ is bivalent C6aryl substituted with four halogen. In some embodiments, L’ is bivalent C6aryl substituted with at least one fluorine. In some embodiments, L’ is bivalent C6aryl substituted with at least two fluorine. In some embodiments, L’ is bivalent C6aryl substituted with at least three fluorine. In some embodiments, L’ is bivalent C6aryl substituted with four fluorine. In some embodiments, L’ is bivalent C6aryl substituted with at least one chlorine. In some embodiments, L’ is bivalent C6aryl substituted with at least two chlorine. In some embodiments, L’ is bivalent C6aryl substituted with at least three chlorine. In some embodiments, L’ is bivalent C6aryl substituted with four chlorine. In some embodiments, L’ is bivalent C6aryl substituted at with least one –O(CH2)0-4CH3. In some embodiments, L’ is bivalent C6aryl substituted with at least two –O(CH2)0-4CH3. In some embodiments, L’ is bivalent C6aryl substituted with at least three –O(CH2)0-4CH3. In some embodiments, L’ is bivalent C6aryl substituted with four –O(CH2)0-4CH3.

[0252] In some embodiments, L’ is bivalent 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, L’ is bivalent 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, L’ is bivalent 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, L’ is bivalent 6 membered heteroaryl ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. Page 117 of 884 12834799v1Attorney Docket Number: 2012675-0389 In some embodiments, L’ is bivalent 6 membered heteroaryl ring having 2 nitrogen.

[0253] In some embodiments, L’ is optionally substituted bivalent C3-20cycloaliphatic ring. In some embodiments, L’ is optionally substituted bivalent C3-15cycloaliphatic ring. In some embodiments, L’ is optionally substituted bivalent C3-10cycloaliphatic ring. In some embodiments, L’ is optionally substituted bivalent C3-9cycloaliphatic ring. In some embodiments, L’ is optionally substituted bivalent C3-8cycloaliphatic ring. In some embodiments, L’ is optionally substituted bivalent C3-7 cycloaliphatic ring. In some embodiments, L’ is optionally substituted bivalent C3-6cycloaliphatic ring. In some embodiments, L’ is optionally substituted bivalent C3-5cycloaliphatic ring. In some embodiments, L’ is optionally substituted bivalent C3-4cycloaliphatic ring. In some embodiments, L’ is optionally substituted bivalent C3cycloaliphatic ring. In some embodiments, L’ is optionally substituted bivalent C4cycloaliphatic ring. In some embodiments, L’ is optionally substituted bivalent C5cycloaliphatic ring. In some embodiments, L’ is optionally substituted bivalent C5cycloalkyl ring. In some embodiments, L’ is optionally substituted bivalent C5cycloalkenyl ring. In some embodiments, L’ is optionally substituted bivalent C6cycloaliphatic ring. In some embodiments, L’ is optionally substituted bivalent C6cycloalkyl ring.

[0254] In some embodiments, Ls2comprises −N(R’)−L’−N(R’)− and L’ is a covalent bond. In some embodiments Ls2comprises −N(R)−N(R)−, wherein: each R is independently −H, or an optionally substituted group selected from C1-30aliphatic, C1-30heteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, C6-30aryl, C6-30arylaliphatic, C6-30arylheteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0255] In some embodiments Ls2comprises −N(R)−N(R)−, wherein: each R is independently optionally substituted C1-30aliphatic; or two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered monocyclic ring.

[0256] In some embodiments, Ls2is a staple selected from the group consisting of: H O ,Page 118 of 884 12834799v1Attorney Docket Number: 2012675-0389 H H H O H H N N N N N N H , diments,Ls1is bivalent C1-6aliphatic. In some embodiments, Ls1is bivalent C1-4aliphatic. In some embodiments, Ls1is saturated. In some embodiments, Ls1is linear. In some embodiments, Ls1is branched. In some embodiments, Ls1is optionally substituted −CH2−. In some embodiments, Ls1is −CH2−. In some embodiments, Ls1is optionally substituted −CH2−CH2−. In some embodiments, Ls1is −CH2−CH2−. In some embodiments, Ls1is optionally substituted −C(CH3)2−. In some embodiments, Ls1is −C(CH3)2−.

[0258] In some embodiments, Ls2is optionally substituted bivalent C1-6, (e.g., C3-6, C3, C4, C5, C6, etc.) aliphatic wherein one or more methylene units are optionally and independently replaced with −Cy− or −C(R’)2−. In some embodiments, Ls2is optionally substituted bivalent C1-6aliphatic. In some embodiments, Ls2is optionally substituted bivalent C3-6aliphatic. In some embodiments, Ls2is bivalent C1-6aliphatic. In some embodiments, Ls2is bivalent C1-4aliphatic. In some embodiments, Ls2is optionally substituted bivalent C2aliphatic. In some embodiments, Ls2is optionally substituted bivalent C3aliphatic. In some embodiments, Ls2is optionally substituted bivalent C4aliphatic. In some embodiments, Ls2is optionally substituted bivalent C5aliphatic. In some embodiments, Ls2is optionally substituted bivalent C6aliphatic. In some embodiments, Ls2is substituted. In some embodiments, Ls2is unsubstituted. In some embodiments, Ls2is saturated. In some Page 119 of 884 12834799v1Attorney Docket Number: 2012675-0389 embodiments, Ls2is linear. In some embodiments, Ls2is branched. In some embodiments, Ls2is optionally substituted bivalent C3-6, (e.g., C3-5, C3, C4, C5, C6, etc.) aliphatic wherein one or two methylene units are independently replaced with −Cy−. In some embodiments, Ls2is −CH2−Cy−CH2−. In some embodiments, Ls2is −CH2−CH2−Cy−CH2−CH2−. In some embodiments, Ls2is −CH2−Cy−Cy−CH2−. Various useful embodiments of −Cy− are as described herein. For example, in some embodiments, −Cy− is an optionally substituted monocyclic 5-membered aromatic ring having 0-4 heteroatoms. In some embodiments, −Cy− is an optionally substituted monocyclic 6-membered aromatic ring having 0-4 heteroatoms. In some embodiments, −Cy− is optionally substituted phenylene. In some embodiments, −Cy− is optionally substituted 1,2-phenylene. In some embodiments, −Cy− is 1,2-phenylene. In some embodiments, −Cy− is optionally substituted 1,3-phenylene. In some embodiments, −Cy− is 1,3-phenylene. In some embodiments, −Cy− is optionally substituted 1,5-phenylene. In some embodiments, −Cy− is 1,5-phenylene. In some embodiments, −Cy− is 3-methyl-1,5-phenylene. In some embodiments, −Cy− is 3-methoxy-1,5-phenylene. In some embodiments, −Cy− is an optionally substituted bivalent pyridyl ring. In some embodiments, −Cy− is N N Cy−embodiments, −Cy− is an optionally substituted bicyclic 10-membered aromatic ring having 0-4 heteroatoms. In some embodiments, −Cy− is an optionally substituted bivalent naphthyl ring. In some embodiments, −Cy− is a bivalent naphthyl ring. In some embodiments, −Cy− is optionally substitut me. 0it is saturated. In some embodiments, −Cy− is an optionally substituted 6-membered cycloalkyl ring. In some embodiments, −Cy− is optionally substitute . In some embodiments, Ls2is optionally substitwherein one or two methylene units are independently replaced with −C(R’)2−. In some embodiments, Ls2is Page 120 of 884 12834799v1Attorney Docket Number: 2012675-0389 −CH2−C(R’)2−CH2−. In some embodiments, the two R’ are taken together with the carbon atom to form an optionally substituted ring as described herein, e.g., an optionally substituted 3-10 (e.g., 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered ring having 0-4 (e.g., 1-4, 0, 1, 2, 3, 4, etc.) heteroatoms. In some embodiments, a ring is saturated. In some embodiments, a ring has one or more heteroatoms. In some embodiments, −C(R’)2− O .

[0059] In some embodiments, Ls2is optionally substituted . In someembodiments, Ls2is optionally substituted . In some embodiments, Ls2is optionally Me N substituted . In some embodiments, Ls2is optionally substituted . In some embodiments, Ls2is optionally substituted ted. In some embodiments, Ls2is optionally substitut . In someOembodiments, Ls2is optionally substitute In some embodiments, Ls2is optionallysubstituted . In some embodiments, Ls2is optionally substitut . In some embodimebstituted −(CH2)4−. In some embodiments, Ls2is opstituted −(CH2)3−. In some embodiments, Ls2is optionally substituted −CH2−CH=CH−CH2−. In some embodiments, Ls2is optionally substituted (E)−CH2−CH=CH−CH2−. In some embodiments, Ls2is optionally substituted −CH2−C(O)−CH2−. In some embodiments, Ls2is optionally substitute meembodiments, Ls2is optionally substitute . In some embodiments, Ls2is optionallyPage 121 of 884 12834799v1Attorney Docket Number: 2012675-0389 O substituted . In some embodiments, Ls2is optionally substituted . In some embodime tuted. In some embodiments, it is unsubstituted. In s odiments,N )3−,and / or −CH2−C(O)−CH2− provide higher binding and / or potency tha , Me OO

[0260] In some embodiments, Ls3is optionally substituted bivalent C1-6aliphatic. In some embodiments, Ls3is bivalent C1-6aliphatic. In some embodiments, Ls3is bivalent C1-4aliphatic. In some embodiments, Ls3is saturated. In some embodiments, Ls3is linear. In some embodiments, Ls3is branched. In some embodiments, Ls3is optionally substituted −CH2−. In some embodiments, Ls3is −CH2−. In some embodiments, Ls3is optionally substituted −CH2−CH2−. In some embodiments, Ls3is −CH2−CH2−. In some embodiments, Ls3is optionally substituted −C(CH3)2−. In some embodiments, Ls3is −C(CH3)2−.

[0261] In some embodiments, an amino acid residue for forming a staple is selected from: O O O O HS OHne.In some embodiments, both amino acid residue for forming a staple are independently residues of these amino acids. In some embodiments, each of Ls1and Ls3is independently −CH2−, −CH2−CH2−, or −C(CH3)2−. In some embodiments, a staple is formed by reacting the thiol groups with a thiol reactive linker compound. In some embodiments, such a linker compound has the structure of LG−Ls2−LG or a salt thereof, wherein each LG is independently a leaving group, e.g., −Br, −I, etc. In some embodiments, each LG is independently −Br or −I. In some embodiments, each LG is −Br. In some embodiments, each LG is −I. In some embodiments, Ls2are of such structures that LG−Ls2−LG (each LG is independently −Br or −I) is a compound selected from: Page 122 of 884 12834799v1Attorney Docket Number: 2012675-0389 Me Br N Br Br Br BrBrr [026 omeembodiments, a peptide and excess equivalents (e.g., about 2-10, 5-10, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.; in some embodiments, 5) of a linker compound were added to a 1:1 DMF : 100 mM Na2CO3pH 8.0 solution and stirred at a suitable temperature, e.g., room temperature for a suitable period of time, in some embodiments, 1-2 hours. In some embodiments, e.g., for relatively weaker electrophiles, excess equivalents (e.g., about 10- 30, 10-20, 10, 20, etc.; in some embodiments, 20) of a metal salt, e.g., Zn(acac)2and an excess equivalents (e.g., about 5-20, 10-15, 10, 15, 20, etc.; in some embodiments, 10-15) of a linker compound were added to a peptide in DMA, and the mixture was stirred for a suitable period of time, e.g., overnight, at a suitable temperature, e.g., 37 °C. In some embodiments, equivalents of Zn(acac)2and linker compounds were doubled, and / or the temperature was increased to 50 °C. In some embodiments, certain linker compounds Br Br Br ns.ing linker moieties (Ls2), e.g., through utilizing other leaving groups or through other reaction mechansms / routes.

[0263] In some embodiments, a staple having the structure of −Ls1−S−Ls2−S−Ls3− is a (i, i+4) staple. In some embodiments, such a staple is in closer to a C-terminus. In some embodiments, such a staple is in closer to a N-terminus. For example, in some embodiments, such a staple is between X10and X14.

[0264] In some embodiments, certain staples provide better properties and / or activities. For example, in some embodiments, based on target binding affinity certain staples / scaffolds is ranked in the following order: Page 123 of 884 12834799v1Attorney Docket Number: 2012675-0389 SLs2 S S Ls2 S S Ls2 S S Ls2 S> n ~ n n > nX3N X N X3N X3N C

[026] s ose s e n e ar w apprec a e, prov e ec no og es can e u ze o prepare collection of peptides using non-cysteine residues and suitable chemistry therefor. For example, in some embodiments, cysteine stapling is replaced with lysine stapling, wherein the cysteine residues for cysteine stapling are replaced with lysine residues for lysine stapling (e.g., using agents that can crosslink two lysine residues, for example, through reactions with side chain amino groups). In some embodiments, for lysine stapling, REin various formulae is or comprises an activated carboxylic acid group (e.g., NHS ester group), an imidoester group, etc. Suitable reagents are widely known in the art including many commercially available ones. In some embodiments, cysteine stapling is replaced with methionine stapling. In some embodiments, cysteine residues for cysteine stapling are replaced with methionine residues for methionine stapling. In some embodiments, cysteine stapling is replaced with tryptophan stapling. In some embodiments, cysteine residues for cysteine stapling are replaced with tryptophan residues for tryptophan stapling. As those skilled in the art will appreciate, various technologies (e.g., reagents, reactions, etc.) are described in the art and can be utilized in accordance with the present disclosure for, e.g., methionine stapling, tryptophan stapling, etc. In some embodiments, such stapling can be performed using reagents having various formulae described herein, wherein REis or comprises a group that are suitable for methionine and / or tryptophan stapling. In some embodiments, stapling may be performed using one residue at a first position, and a different residue at a second position. Useful reagents for such stapling may comprise a first reactive group for stapling at a first position (e.g., through a first RE), and a second reactive group for stapling at a second position (e.g., through a second RE).

[0266] In some embodiments, for various types of stapling (e.g., cysteine stapling, or non-cysteine stapling), stapling is between residues (e.g., cysteine residues for cysteine stapling) separated by two residues (i+3 stapling). In some embodiments, stapling is between residues separated by three residues (i+4 stapling). In some embodiments, stapling is between residues separated by six residues (i+7 stapling).

[0267] As appreciated by those skilled in the art, in some embodiments, more than two residues can be stapled at the same time. For example, in some embodiments, three or more cysteines are stapled using crosslinking reagents containing three or more reactive groups (e.g., REgroups).

[0268] In some embodiments, as described herein, the present disclosure provides useful technologies relating to non-cysteine stapling. Among other things, the present disclosure appreciates that peptides amenable to cysteine stapling and / or comprising one or more non-cysteine staples, can have its cysteine residues and cysteine staple replaced with other amino acids and staples described herein (e.g. hydrocarbon and other non-hydrocarbon amino acid and staples). In some embodiments, the resulting non-cysteine stapled peptide maintains the same or similar interaction with a target of interest when compared to a reference Page 124 of 884 12834799v1Attorney Docket Number: 2012675-0389 cysteine stapled peptide.

[0269] Many technologies, e.g., reactive groups such as amino groups, −SH, alkynyl, azide, etc., and reactions involving amino groups such as amidation, click chemistry, reactions involving −SH groups, etc., may be utilized for connecting a moiety, e.g., TBM, to another moiety, the rest of an agent, e.g., −L0−LBM. As demonstrated herein, in some embodiments, TBM is bonded to the rest of an agent, e.g., −L0−LBM, at the N-terminal of a polypeptide (e.g., through an amide group formed with the N-terminal amine group). In some embodiments, TBM is bonded to the rest of an agent, e.g., −L0−LBM, at an amino acid residue. In some embodiments, an amino acid residue is the first amino acid residue from the N-terminus. In some embodiments, an amino acid residue is the last amino acid residue from the N-terminus. In some embodiments, an amino acid residue is not the first or last amino acid residue from the N-terminus. In some embodiments, the backbone of an amino acid residue is bonded to the rest of an agent, e.g., −L0−LBM. In some embodiments, the side chain of an amino acid residue is bonded to the rest of an agent, e.g., −L0−LBM. For example, in some embodiments, the side chain of an amino acid residue comprises an amino group, and an amino acid residue is bonded to the rest of an agent, e.g., −L0−LBM, through, e.g., an amide group formed with the amino group. In some embodiments, the side chain of an amino acid residue comprises −NHR, wherein R is −H or optionally substituted C1-6aliphatic, and −NHR is utilized to bond to the rest of an agent, e.g., −L0−LBM (e.g., by formation of an amide group). In some embodiments, such −NHR is −NH2. In some embodiments, an amino acid residue is Lys and is bonded to −L0−LBM through, e.g., an amide group formed with the −NH2group of the side chain. In some embodiments, an amino acid residue is dLys and is bonded to −L0−LBM through, e.g., an amide group formed with the −NH2group. In some embodiments, an amino acid residue is PyrSa and is bonded to −L0−LBM through, e.g., an amide group formed with the amino group of the side chain. In some embodiments, an amino acid residue is 4PipS and is bonded to −L0−LBM through, e.g., an amide group formed with the amino group of the side chain. In some embodiments, an amino acid residue is 1MeK and is bonded to −L0−LBM through, e.g., an amide group formed with the amino group of the side chain. In some embodiments, an amino acid residue is Dap and is bonded to −L0−LBM through, e.g., an amide group formed with the amino group of the side chain. In some embodiments, an amino acid residue is Dab and is bonded to −L0−LBM through, e.g., an amide group formed with the amino group of the side chain. In some embodiments, an amino acid residue is Acp and is bonded to −L0−LBM through, e.g., an amide group formed with the amino group of the side chain. In some embodiments, an amino acid residue is Aza and is bonded to −L0−LBM through, e.g., an amide group formed with the amino group of the side chain. In some embodiments, the side chain of an amino acid residue comprises a moiety formed by reaction of an azide group with an alkyne group. In some embodiments, an amino acid residue is TriAzLys and is bonded to N −L0−LBM through theN Nmoiety of the side chain. In some embodiments, the side chain of an Page 125 of 884 12834799v1Attorney Docket Number: 2012675-0389 N amino acid residue comprises an alkynyl group, and is bonded to −L0−LBM through, e.g., aN Nmoiety formed with −N3. In some embodiments, the side chain of an amino acid residue c azideN group, and is bonded to −L0−LBM through, e.g., aN Nmoiety formed with an alkynyl group. In some embodiments, the side chain of amino acid rises −SH and is bonded to the rest of the 0agent, .g., −L −LBM, at the side chain (e.g., by formation of a thioester group). In some embodiments, an amino acid residue is Cys and is bonded to −L0−LBM through, e.g., a thioester group formed with the −SH group of the side chain. In some embodiments, an amino acid residue is Pen and is bonded to −L0−LBM through, e.g., a thioester group formed with the −SH group of the side chain.

[0270] In some embodiments, a peptide, e.g., PTBM, has the structure of formula I: RN−LP1−LAA1−LP2−LAA2−LP3−LAA3−LP4−LAA4−LP5−LAA5−LP6−LAA6−LP7−RC, I or a salt thereofRNis a peptide, an amino protecting group or R’−LRN−; each of LP1, LP2, LP3, LP4, LP5, LP6, and LP7is independently L, wherein LP1, LP2, LP3, LP4, LP5, LP6, and LP7comprise: a first R’ group and a second R’ group which are taken together to form −Ls− which is bonded to the atom to which a first R’ group is attached and the atom to which a second R’ group is attached; and a third R’ group and a fourth R’ group which are taken together to form −Ls− which is bonded to the atom to which a third R’ group is attached and the atom to which a fourth R’ group is attached; each Lsis independently −Ls1−Ls2−Ls3−, wherein each Ls1, Ls2and Ls3is independently L; LAA1is an amino acid residue that comprises a side chain comprising an acidic or polar group; LAA2is an amino acid residue that comprises a side chain comprising an acidic or polar group; LAA3is an amino acid residue; LAA4is an amino acid residue that comprises a side chain comprising an optionally substituted aromatic group; LAA5is an amino acid residue that comprises a side chain comprising an optionally substituted aromatic group; LAA6is an amino acid residue that comprises a side chain comprising an optionally substituted aromatic group; RCis a peptide, a carboxyl protecting group, −LRC−R’, −O−LRC−R’ or −N(R’)−LRC−R’; each of LRNand LRCis independently L; Page 126 of 884 12834799v1Attorney Docket Number: 2012675-0389 each L is independently a covalent bond, or an optionally substituted, bivalent C1-C25aliphatic or heteroaliphatic group having 1-10 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−; each −Cy− is independently an optionally substituted bivalent, 3-30 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms; each R’ is independently −L−R, −C(O)R, −CO2R, or −SO2R; each R is independently −H, or an optionally substituted group selected from C1-30aliphatic, C1-30heteroaliphatic having 1-10 heteroatoms, C6-30aryl, C6-30arylaliphatic, C6-30arylheteroaliphatic having 1-10 heteroatoms, 5-30 membered heteroaryl having 1-10 heteroatoms, and 3-30 membered heterocyclyl having 1- 10 heteroatoms, or two R groups are optionally and independently taken together to form a covalent bond, or: two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms; or two or more R groups on two or more atoms are optionally and independently taken together with their intervening atom(s) to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atom(s), 0-10 heteroatoms.

[0271] In some embodiments, a peptide, e.g., PTBM, has the structure of formula I: RN−LP1−LAA1−LP2−LAA2−LP3−LAA3−LP4−LAA4−LP5−LAA5−LP6−LAA6−LP7−RC,I or a salt thereof, wherein: RNis a peptide, an amino protecting group or R’−LRN−; each of LP1, LP2, LP3, LP4, LP5, LP6, and LP7is independently L, wherein LP1, LP2, LP3, LP4, LP5, LP6, and LP7comprise: a first R’ group and a second R’ group which are taken together to form −Ls− which is bonded to the atom to which a first R’ group is attached and the atom to which a second R’ group is attached; and a third R’ group and a fourth R’ group which are taken together to form −Ls− which is bonded to the atom to which a third R’ group is attached and the atom to which a fourth R’ group is attached; each Lsis independently −Ls1−Ls2−Ls3−, wherein each Ls1, Ls2and Ls3is independently L; LAA1is LAR, wherein a methylene unit is replaced with −C(R’)(RAS)−, wherein RASis −LAS1−RAA1, wherein RAA1is −CO2R or −SO2R; LAA2is LAR, wherein a methylene unit is replaced with −C(R’)(RAS)−, wherein RASis −LAS2−RAA2, Page 127 of 884 12834799v1Attorney Docket Number: 2012675-0389 wherein RAA2is −CO2R or −SO2R; LAA3is LAR, wherein a methylene unit is replaced with −C(R’)(RAS)−, wherein RASis −LAS3−RAA3, wherein RAA3is R’; LAA4is LAR, wherein a methylene unit is replaced with −C(R’)(RAS)−, wherein RASis −LAS4−RAA4, wherein RAA4is an optionally substituted group selected from 6-14 membered aryl or 5-14 membered heteroaryl having 1-6 heteroatoms; LAA5is LAR, wherein a methylene unit is replaced with −C(R’)(RAS)−, wherein RASis −LAS5−RAA5, wherein RAA5is an optionally substituted group selected from 6-14 membered aryl or 5-14 membered heteroaryl having 1-6 heteroatoms; LAA6is LAR, wherein a methylene unit is replaced with −C(R’)(RAS)−, wherein RASis −LAS6−RAA6, wherein RAA6is an optionally substituted group selected from 6-14 membered aryl or 5-14 membered heteroaryl having 1-6 heteroatoms; RCis a peptide, a carboxyl protecting group, −LRC−R’, −O−LRC−R’ or −N(R’)−LRC−R’; each of LRNand LRCis independently L; each LARis independently an optionally substituted, bivalent C1-C4aliphatic group, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −C(R’)(RAS)−,−Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−; each of LAS1, LAS2, LAS3, LAS4, LAS5, and LAS6is independently LAS; each RASis independently −LAS−R’; each LASis independently an optionally substituted, bivalent C1-C10aliphatic or heteroaliphatic group having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−; each L is independently a covalent bond, or an optionally substituted, bivalent C1-C25aliphatic or heteroaliphatic group having 1-10 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−; each −Cy− is independently an optionally substituted bivalent, 3-30 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms; each R’ is independently −L−R, −C(O)R, −CO2R, or −SO2R; each R is independently −H, or an optionally substituted group selected from C1-30aliphatic, C1-30heteroaliphatic having 1-10 heteroatoms, C6-30aryl, C6-30arylaliphatic, C6-30arylheteroaliphatic having 1-10 heteroatoms, 5-30 membered heteroaryl having 1-10 heteroatoms, and 3-30 membered heterocyclyl having 1- 10 heteroatoms, or Page 128 of 884 12834799v1Attorney Docket Number: 2012675-0389 two R groups are optionally and independently taken together to form a covalent bond, or: two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms; or two or more R groups on two or more atoms are optionally and independently taken together with their intervening atom(s) to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atom(s), 0-10 heteroatoms.

[0272] In some embodiments, a second R’ group and a third R’ group are attached to the same atom. In some embodiments, none of the first, second and fourth R’ groups are attached to the same atom. In some embodiments, none of the first, second, fourth, fifth and sixth R’ groups are attached to the same atom. In some embodiments, none of the first, second, fourth, fifth, sixth, seventh and eighth R’ groups are attached to the same atom. In some embodiments, each of the first, second, third and fourth R’ groups is independently attached to a different atom. In some embodiments, each of the first, second, third, fourth, fifth and sixth R’ groups is independently attached to a different atom. In some embodiments, each of the first, second, third, fourth, fifth, sixth, seventh and eighth R’ groups is independently attached to a different atom.

[0273] In some embodiments, a compound of formula I, e.g., PTBM, is a stapled peptide as described herein.

[0274] In some embodiments, each Lsis independently a staple as described herein. In some embodiments, Ls, e.g., Lsformed by taking a first and a second R’ groups, has a length of 5-20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) atoms. Unless specified otherwise, a length between two connection sites, e.g., of Ls, L, etc., is the shortest covalent connection from one site to the other. For example, the length of −CH2−CH2− is 2 atoms (−C−C−), the length of 1, 3-phenylene is 3 atoms. In some embodiments, Ls, e.g., Lsformed by taking a third and a fourth R’ groups, has a length of 5-20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) atoms. In some embodiments, Ls, e.g., Lsformed by taking a fifth and a sixth R’ groups, has a length of 5-20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) atoms. In some embodiments, Ls, e.g., Lsformed by taking a seventh and an eighth R’ groups, has a length of 5-20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) atoms.

[0275] Those skilled in the art reading the present disclosure will appreciate that staples, e.g., Ls, connecting two atoms having a longer distance typically has a longer length than staples connecting two atoms having a shorter distance, e.g., (i, i+7) staples typically have longer lengths than (i, i+3) or (i, i+4) staples. In some embodiments, a length is 5 atoms. In some embodiments, a length is 6 atoms. In some embodiments, a length is 7 atoms. In some embodiments, a length is 8 atoms. In some embodiments, a length is 9 atoms. In some embodiments, a length is 10 atoms. In some embodiments, a length is 11 atoms. In some embodiments, a length is 12 atoms. In some embodiments, a length is 13 atoms. In some embodiments, a length is 14 atoms. In some embodiments, a length is 15 atoms. In some embodiments, a length is 16 atoms. In some embodiments, a length is 17 atoms. In some embodiments, a length is 18 atoms. In some Page 129 of 884 12834799v1Attorney Docket Number: 2012675-0389 embodiments, a length is 19 atoms. In some embodiments, a length is 20 atoms. LP1

[0276] In some embodiments, LP1is a covalent bond, or an optionally substituted, bivalent C2-C6aliphatic group, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−. In some embodiments, the length of LP1is 2-10 atoms. In some embodiments, it is 2 atoms. In some embodiments, it is 3 atoms. In some embodiments, it is 4 atoms. In some embodiments, it is 5 atoms. In some embodiments, it is 6 atoms. In some embodiments, it is 7 atoms. In some embodiments, it is 8 atoms. In some embodiments, it is 9 atoms. In some embodiments, it is 10 atoms. In some embodiments, one or more methylene units are independently replaced with −N(R’)−, −C(R’)2−, −C(O)− or −C(O)N(R’)−. In some embodiments, a methylene unit is replace with −N(R’)−. In some embodiments, a methylene unit is replace with −C(R’)2−. In some embodiments, a methylene unit is replace with −C(O)−. In some embodiments, a methylene unit is replace with −C(O)N(R’)−. In some embodiments, each methylene unit is independently replaced with −N(R’)−, −C(R’)2− or −C(O)−. In some embodiments, LP1is or comprises an amino acid residue. In some embodiments, LP1is or comprises a peptide.

[0277] In some embodiments, LP1is or comprises −[X]p−X1−, wherein each of p, X and X1is independently as described herein, and X1is bonded to LAA1. In some embodiments, LP1is or comprises −X1−.

[0278] In some embodiments, LP1comprises a −C(R’)2− group, wherein one of the R’ groups is a first R’ group of the four. In some embodiments, such a −C(R’)2− group is of an amino acid residue. In some embodiments, such a −C(R’)2− group is of X1. In some embodiments, such a carbon atom is an alpha carbon of an amino acid residue. LAA179] In some embodiments, LAA1is or comprises amino acid residue. In some embodiments, LAA1is or comprises an amino acid residue that comprises a side chain comprising an acidic or polar group. In some embodiments, LAA1is an amino acid residue that comprises a side chain comprising an acidic group.

[0280] In some embodiments, LAA1is LAR, wherein a methylene unit is replaced with −C(R’)(RAS)−, wherein each variable is independently as described herein. In some embodiments, LAA1is an optionally substituted, bivalent C1-C6(e.g., C1, C2, C3, C4, C5, or C6) aliphatic group, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −C(R’)(RAS)−,−Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−, wherein each variable is independently as described herein. In some embodiments, LAA1is an optionally substituted, bivalent C2-C4aliphatic group, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −C(R’)(RAS)−,−Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, Page 130 of 884 12834799v1Attorney Docket Number: 2012675-0389 −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−, wherein each variable is independently as described herein. In some embodiments, LAA1is −N(R’)−C(R’)(RAS)−C(O)−, wherein each variable is independently as described herein. In some embodiments, LAA1is −NH−C(R’)(RAS)−C(O)−, wherein each variable is independently as described herein.

[0281] In some embodiments, LAS1is LASas described herein. In some embodiments, RAA1is −CO2R, wherein R is as described herein. In some embodiments, R is H. In some embodiments, LAA1is a residue of an acidic amino acid residue, e.g., Asp, Glu, etc. In some embodiments, LAA1is X2as described herein. LP2

[0282] In some embodiments, LP2is a covalent bond, or an optionally substituted, bivalent C2-C6aliphatic group, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−. In some embodiments, the length of LP2is 2-10 atoms. In some embodiments, it is 2 atoms. In some embodiments, it is 3 atoms. In some embodiments, it is 4 atoms. In some embodiments, it is 5 atoms. In some embodiments, it is 6 atoms. In some embodiments, it is 7 atoms. In some embodiments, it is 8 atoms. In some embodiments, it is 9 atoms. In some embodiments, it is 10 atoms. In some embodiments, one or more methylene units are independently replaced with −N(R’)−, −C(R’)2−, −C(O)− or −C(O)N(R’)−. In some embodiments, a methylene unit is replace with −N(R’)−. In some embodiments, a methylene unit is replace with −C(R’)2−. In some embodiments, a methylene unit is replace with −C(O)−. In some embodiments, a methylene unit is replace with −C(O)N(R’)−. In some embodiments, each methylene unit is independently replaced with −N(R’)−, −C(R’)2− or −C(O)−. In some embodiments, LP2is or comprises an amino acid residue. In some embodiments, LP2is or comprises a peptide.

[0283] In some embodiments, LP2is or comprises −[X]pX4[X]p’−, wherein each of p, p’, X and X4is independently as described herein. In some embodiments, LP2is or comprises −[X]pX3X4[X]p’−, wherein each X, X3and X4is independently an amino acid residue, and each of p and p’ is independently 0-10. In some embodiments, LP2is or comprises −X3X4−, wherein each X3and X4is independently as described herein, and X4is bonded to LAA2.

[0284] In some embodiments, LP2comprises a −C(R’)2− group, wherein one of the R’ groups is a second R’ group and the other is a third of the four. In some embodiments, such a −C(R’)2− group is of an amino acid residue. In some embodiments, such a −C(R’)2− group is of X4. In some embodiments, such a carbon atom is an alpha carbon of an amino acid residue. In some embodiments, such a carbon atom is an alpha carbon of X4.

[0285] In some embodiments, a methylene unit of LP2is replaced with −C(R’)2−, wherein one of the R’ groups is a second or fifth or seventh R’ group. In some embodiments, such a −C(R’)2− group is of an amino acid residue. In some embodiments, such a −C(R’)2− group is of X3. In some embodiments, such a carbon atom is an alpha carbon of an amino acid residue. In some embodiments, such a carbon atom is an alpha Page 131 of 884 12834799v1Attorney Docket Number: 2012675-0389 carbon of X3. In some embodiments, it is a second R’ group. In some embodiments, it is a fifth R’ group. In some embodiments, it is a seventh R’ group.

[0286] In some embodiments, a methylene unit of LP2is replaced with −C(R’)2−, wherein one of the R’ groups is a first or third R’ group. In some embodiments, such a −C(R’)2− group is of an amino acid residue. In some embodiments, such a −C(R’)2− group is of X4. In some embodiments, such a carbon atom is an alpha carbon of an amino acid residue. In some embodiments, such a carbon atom is an alpha carbon of X4. In some embodiments, it is a first R’ group. In some embodiments, it is a third R’ group. LAA2

[0287] In some embodiments, LAA2is or comprises amino acid residue. In some embodiments, LAA2is or comprises an amino acid residue that comprises a side chain comprising an acidic or polar group. In some embodiments, LAA2is an amino acid residue that comprises a side chain comprising an acidic group.

[0288] In some embodiments, LAA2is LAR, wherein a methylene unit is replaced with −C(R’)(RAS)−, wherein each variable is independently as described herein. In some embodiments, LAA2is an optionally substituted, bivalent C1-C6(e.g., C1, C2, C3, C4, C5, or C6) aliphatic group, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −C(R’)(RAS)−,−Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−, wherein each variable is independently as described herein. In some embodiments, LAA2is an optionally substituted, bivalent C2-C4aliphatic group, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −C(R’)(RAS)−,−Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−, wherein each variable is independently as described herein. In some embodiments, LAA2is −N(R’)−C(R’)(RAS)−C(O)−, wherein each variable is independently as described herein. In some embodiments, LAA2is −NH−C(R’)(RAS)−C(O)−, wherein each variable is independently as described herein.

[0289] In some embodiments, LAS2is LASas described herein. In some embodiments, RAA2is −CO2R, wherein R is as described herein. In some embodiments, R is H. In some embodiments, LAA2is a residue of an acidic amino acid residue, e.g., Asp, Glu, etc. In some embodiments, LAA2is X5as described herein. LP3

[0290] In some embodiments, LP3is a covalent bond. In some embodiments, LP3is an optionally substituted, bivalent C2-C6aliphatic group, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−. In some embodiments, the length of LP3is 0-10 atoms. In some embodiments, the length of LP3is 2-10 atoms. In some embodiments, it is 2 atoms. In some embodiments, it is 3 atoms. In some embodiments, it is 4 atoms. In some embodiments, it is 5 atoms. In some embodiments, it is 6 atoms. In some embodiments, it is 7 atoms. In some embodiments, it is 8 atoms. In some embodiments, it is 9 atoms. In some embodiments, Page 132 of 884 12834799v1Attorney Docket Number: 2012675-0389 it is 10 atoms. In some embodiments, one or more methylene units are independently replaced with −N(R’)−, −C(R’)2−, −C(O)− or −C(O)N(R’)−. In some embodiments, a methylene unit is replace with −N(R’)−. In some embodiments, a methylene unit is replace with −C(R’)2−. In some embodiments, a methylene unit is replace with −C(O)−. In some embodiments, a methylene unit is replace with −C(O)N(R’)−. In some embodiments, each methylene unit is independently replaced with −N(R’)−, −C(R’)2− or −C(O)−. In some embodiments, LP3is or comprises an amino acid residue. In some embodiments, LP3is or comprises a peptide. In some embodiments, LP3is or comprises −[X]pX6X7[X]p’−, wherein each X, X6and X7is independently an amino acid residue, and each of p and p’ is independently 0-10. In some embodiments, LP3is or comprises −X6X7−, wherein each X6and X7is independently an amino acid residue. In some embodiments, X7is bonded to LAA3. In some embodiments, a methylene unit of LP3is replaced with −C(R’)2−, wherein one of the R’ groups is the fifth, sixth, seventh or eighth R’ group. In some embodiments, X7comprises −C(R’)2−, wherein one of the R’ groups is the fifth, sixth, seventh or eighth R’ group. LAA3

[0291] In some embodiments, LAA3is or comprises amino acid residue. In some embodiments, LAA3is or comprises an amino acid residue that comprises a side chain comprising an acidic or polar group. In some embodiments, LAA3is an amino acid residue that comprises a side chain comprising an acidic group.

[0292] In some embodiments, LAA3is LAR, wherein a methylene unit is replaced with −C(R’)(RAS)−, wherein each variable is independently as described herein. ...

Claims

Attorney Docket Number: 2012675-0389 CLAIMS 1. An agent, wherein the agent has the structure of: TBM-L0-LBM, or a salt thereof, wherein: TBM is TBM is –[PTBM], wherein PTBMis of structure: NH2O S S HN OOH O ,Page 828 of 884 12834799v1Attorney Docket Number: 2012675-0389 OOHO ,Page 829 of 884 12834799v1Attorney Docket Number: 2012675-0389 NH2 H2N OO S HO NH HN O, ,Page 830 of 884 12834799v1Attorney Docket Number: 2012675-0389 S S H N O H ,Page 831 of 884 12834799v1Attorney Docket Number: 2012675-0389 NH2NH2O S O S HN O HN OOH ; ouphaving 1-12 heteroatoms, wherein one or more methylene units of the group are each optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, −C(O)O−, −(OCH2CH2)n−, or an amino acid residue; n is 1-20; and LBM is an E3 ubiquitin ligase binding moiety, or LBM is of formula II, III, IV, V, VI or VII: RRAnA wherein:Ring A1is an optionally substituted 3-30 membered ring having 0-10 heteroatoms; each RRAis independently R’; nA is 0, 1, 2, 3, or 4; rA is 0 or 1; LAis L; Page 832 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O ZNH Z Nomeach Rais independently R ;each R’ is independently −R, −C(O)R, −CO2R, or −SO2R; each R is independently −H, or an optionally substituted group selected from C1-30aliphatic, C1-30heteroaliphatic having 1-10 heteroatoms, C6-30 aryl, C6-30 arylaliphatic, C6-30 arylheteroaliphatic having 1-10 heteroatoms, 5-30 membered heteroaryl having 1-10 heteroatoms, and 3-30 membered heterocyclyl having 1- 10 heteroatoms; or two R groups are optionally and independently taken together to form a covalent bond, or: two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered ring having, in addition to the atom, 0-10 heteroatoms; or two or more R groups on two or more atoms are optionally and independently taken together with their intervening atom(s) to form an optionally substituted, 3-30 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms; each L is independently a covalent bond or an optionally substituted bivalent C1-C6aliphatic or heteroaliphatic group having 1-10 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−; and each −Cy− is independently an optionally substituted bivalent 3-30 membered ring having 0-10 heteroatoms; (RRC)nC (RRD)nD, Page 833 of 884 12834799v1Attorney Docket Number: 2012675-0389 wherein: Ring B, Ring C, and Ring D are each independently an optionally substituted 3-30 membered ring having 0-10 heteroatoms; RBis R’; LB, LBC, and LCDare each independently L; each RRBis independently −OR’ or R’; each RRCis independently R’; each RRDis independently R’; and each of nB, nC and nD is independently 0, 1, 2, 3, or 4; RIVH O N wherein RIVis R’;LE(RRF)EFnF L wherein:LE, LEF, and LGHare each independently L; Ring E, Ring F, Ring G, and Ring H are each independently an optionally substituted 3-30 membered ring having 0-10 heteroatoms; each of RRE, RRF, RRG, and RRHis independently R’; and each of nE, nF, nG, and nH is independently 0, 1, 2, 3, or 4; (RRJ) JJO n wherein:Page 834 of 884 12834799v1Attorney Docket Number: 2012675-0389 Ring J is an optionally substituted 3-30 membered ring having 0-10 heteroatoms; each RRJis independently R’; and nJ is 0, 1, 2, 3, or 4; (RRL)nLL wherein: Ring K and Ring L are each independently an optionally substituted 3-30 membered ring having 0-10 heteroatoms; LKLis L; each of RRKand RRLis independently R’; and each of nK and nL is independently 0, 1, 2, 3, or 4; O H O N N OH wherein RVIIIis R’;O ; 2. An agent, wherein the age- - , or a salt thereof, wherein: TBM is a target binding agent; L0is a covalent bond or an optionally substituted, bivalent C1-C30aliphatic or heteroaliphatic group having 1-12 heteroatoms, wherein one or more methylene units of the group are each optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, −C(O)O−, −(OCH2CH2)n−, or an amino acid residue; n is 1-20; and Page 835 of 884 12834799v1Attorney Docket Number: 2012675-0389 LBM is an E3 ubiquitin ligase binding moiety, or LBM is of formula II, III, IV, V, VI or VII: RRAnA wherein: Ring A1is an optionally substituted 3-30 membered ring having 0-10 heteroatoms; each RRAis independently R’; nA is 0, 1, 2, 3, or 4; rA is 0 or 1; LAis L; O O ZNH Z Nomeach Rais independently R’; each R’ is independently −R, −C(O)R, −CO2R, or −SO2R; each R is independently −H, or an optionally substituted group selected from C1-30aliphatic, C1-30heteroaliphatic having 1-10 heteroatoms, C6-30aryl, C6-30arylaliphatic, C6-30arylheteroaliphatic having 1-10 heteroatoms, 5-30 membered heteroaryl having 1-10 heteroatoms, and 3-30 membered heterocyclyl having 1- 10 heteroatoms; or two R groups are optionally and independently taken together to form a covalent bond, or: two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered ring having, in addition to the atom, 0-10 heteroatoms; or two or more R groups on two or more atoms are optionally and independently taken together with their intervening atom(s) to form an optionally substituted, 3-30 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms; Page 836 of 884 12834799v1Attorney Docket Number: 2012675-0389 each L is independently a covalent bond or an optionally substituted bivalent C1-C6aliphatic or heteroaliphatic group having 1-10 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−; and each −Cy− is independently an optionally substituted bivalent 3-30 membered ring having 0-10 heteroatoms; (RRC)nC(RRD)nD LCDwherein: Ring B, Ring C, and Ring D are each independently an optionally substituted 3-30 membered ring having 0-10 heteroatoms; RBis R’; LB, LBC, and LCDare each independently L; each RRBis independently −OR’ or R’; each RRCis independently R’; each RRDis independently R’; and each of nB, nC and nD is independently 0, 1, 2, 3, or 4; RIVH Owherein RIVis R’; Page 837 of 884 12834799v1Attorney Docket Number: 2012675-0389 ERF EFL (R )nFL E wherein: LE, LEF, and LGHare each independently L; Ring E, Ring F, Ring G, and Ring H are each independently an optionally substituted 3-30 membered ring having 0-10 heteroatoms; each of RRE, RRF, RRG, and RRHis independently R’; and each of nE, nF, nG, and nH is independently 0, 1, 2, 3, or 4; RJO (R )nJ Jwherein:Ring J is an optionally substituted 3-30 membered ring having 0-10 heteroatoms; each RRJis independently R’; and nJ is 0, 1, 2, 3, or 4; (RRL)nL L wherein:Ring K and Ring L are each independently an optionally substituted 3-30 membered ring having 0-10 heteroatoms; LKLis L; each of RRKand RRLis independently R’; and each of nK and nL is independently 0, 1, 2, 3, or 4; Page 838 of 884 12834799v1Attorney Docket Number: 2012675-0389 O H O N N OH H wherein RVIIIis R’;O H ; 3. The agent of any one of cl a III:(RRC)nC(RRD)nD LCD4. The agent of any onRC(RRD)nD R, wherein RB2is selected from C3-6alkyl and -NHC(O)CH3; and RBCis hydrogen or C1-6alkyl; optionally wherein the moiety or Ring C is optionally substituted phenyl.

5. The agent of any one, formula: Page 839 of 884 12834799v1Attorney Docket Number: 2012675-0389 R S (RC)nC (RRD)nDRBCCDN L N , .: Page 840 of 884 12834799v1Attorney Docket Number: 2012675-0389 S S N N , N ,Page 841 of 884 12834799v1Attorney Docket Number: 2012675-0389 N S S N F , N , N ,Page 842 of 884 12834799v1Attorney Docket Number: 2012675-0389 N S S S ,RRAnA 8. The agent of claim 7, whereinoptionally substituted C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −O−, −S−, −N(R)−, −N=N−, −C(O)−, −C(S)−, −C(NR)−, −C(NOR)−, −C(NNR2)−, −OC(O)−, −C(O)O−, −C(O)N(R)−, −N(R)C(O)−, −C(NR)O−, −OC(NR)−, −C(NR)NR−, −N(R)C(NR)−, −N(R)C(O)N(R)−, −N(R)C(O)O−, −OC(O)N(R)−, −N(R)C(O)S−, −SC(O)N(R)−, −N(R)C(NR)N(R)−, −S(O)−, −SO2−, −SO2N(R)−, −N(R)SO2−, or −Cy−. O 9. The agent of any one of claims 7-8, wherein Ring A2is optionally substitute or Ooptionally substituted or wherein Ring A1is optionally substituted phenyl or optionallyPage 843 of 884 12834799v1Attorney Docket Number: 2012675-0389 substituted 5- to 16-membered ring having 1-6 heteroatoms independently selected from N, O, and S, or wherein Ring A1is selected from: * * O * O O N N N ,whereinptona y w ere n t ere s no optona substtuent on any nitroge *represents a point of connection too n atom of Ring A2.

10. The agent of any one of claims 1-2, wherein LBM is of a structure selected from: O HN ,RIVH ORIVH O optionally wherein LBM is of formula ,Page 844 of 884 12834799v1Attorney Docket Number: 2012675-0389 optionally wherein RIVN is -CH2-phenyl, -CH2CH(CH3)2-CH2CH2CH2CH2NH2-CH2CH2CH2NHC(NH)NH2or HN , or whereiN and 12.O H O N N OH13. The agent of any one of claims 1-2, wherein LBM is of formula IX: O 14. The agent of any one of clre: Page 845 of 884 12834799v1Attorney Docket Number: 2012675-0389 OO.

15. The agent of any one o VI:O (RRJ)nJJoptionally wherein RRJis -O nally wherein LBM is of structure:O O .

16. The agent of any one of claimsrmula VII: (RRL)nL Loptionally wherein LBM is of structure: O .

17. The agent of any one of the pece g c a s, w e e s of formula: a LbcLdLL*wherein:La, Lb, Lc, and Ldare each independently a covalent bond or an optionally substituted, bivalent C1-C7aliphatic or heteroaliphatic group having 1-3 heteroatoms, wherein one or more methylene units of the group are each optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, Page 846 of 884 12834799v1Attorney D *ocket Number: 2012675-0389 −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, −C(O)O−, −(OCH2CH2)n− or an amino acid residue; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and represents a point of connection to LBM. O n 18. The agent of claim 17, wherein Lbis m 2a2selected from N, O, and S.

22. The agent of claim 17, wherein L0is of formula: LaOc *, wherein m is 0, 1, 2, 3, 4, 5, or 6.

19. The agent of any one of claims 17- s a covalent bond, -CH2-, -C(O)-, -CH2C(O)NH-, or -C(O)(CH ) -Cya-, wherein a is 0, 1, 2, or 3 and Cyais an optionally substituted bivalent 3-30 membered ring having 0-10 heteroatoms.

20. The agent of any one of claims 17-19, wherein Lcis a covalent bond, -O-, -CH2O-, -OCH2-, -C(O)-, -N(H)C(O)-, -N(CH3)C(O)- or an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S.

21. The agent of any one of claims 17-20, wherein Ldis a covalent bond, -CH2-, -C(O)-, -C(O)CH2- , -NH-, -CH NH-, or an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently LdL * mnwherein:m is 0, 1, 2, 3, 4, 5, or 6; Lais a covalent bond, -CH2-, -C(O)-, -CH2C(O)NH-, or an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; Lcis a covalent bond, -O-, -CH2O-, -OCH2-, -C(O)-, -N(H)C(O)-, -N(CH3)C(O)-, or an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; and Ldis a covalent bond, -CH2-, -C(O)-, -C(O)CH2-, -NH-, -CH2NH-, or an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S.

23. The agent of claim 22, wherein: Lais -C(O)-; m is 0, 1, 2, or 3; Lcis a covalent bond, -O-, -N(H)C(O)-, -N(CH3)C(O)-, or a 3- to 6-membered cycloalkyl or heterocyclyl ring having 0-2 heteroatoms independently selected from N, O, and S; and Ldis -CH2- or -C(O)CH2-.

24. The agent of claim 17, wherein L0is of formula: O * .Page 847 of 884 12834799v1Attorney Docket Number: 2012675-0389 25. The agent of any one of claims 1-17, wherein L0is or comprises O O O OO *OOO O** ,Page 848 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O H H H H N N N N * * , , * ,Page 849 of 884 12834799v1Attorney Docket Number: 2012675-0389 * OHN O NHH NN* ,*,12834799v1Attorney Docket Number: 2012675-0389 H H O O O ON *O O O O ON,*, * ,Pa * , * , ge 851 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O OONOOO N*NNNNO *, * ¸Page 852 of 884 12834799v1Attorney Docket Number: 2012675-0389 O O O * O O O N N N *2 2 2 2 2 2 2* , −C(O)−CH−(OCHCH)n−N(R)−, −C(O)−CH−(OCHCH)n−N(R)−C(O)−CH−, wherein n is 0-10 (e.g., 0, 1-10, 1-5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.). O H H NN N N* 26. The agent of any one of claims 1-16, wherei , O H N* ,age 853 o 88 12834799v1Attorney Docket Number: 2012675-0389 H H O N O N O O* OO O O O of27. The agent of any one of claims 2-26, wherein TBM is –[P ], wherein P has the structure of formula I: RN−LP1−LAA1−LP2−LAA2−LP3−LAA3−LP4−LAA4−LP5−LAA5−LP6−LAA6−LP7−RC, Ior a salt thereof, wherein: RNis a peptide, an amino protecting group or R’−LRN−; each of LP1, LP2, LP3, LP4, LP5, LP6, and LP7is independently L, wherein LP1, LP2, LP3, LP4, LP5, LP6, and LP7comprise: a first R’ group and a second R’ group which are taken together to form −Ls− which is bonded to the atom to which a first R’ group is attached and the atom to which a second R’ group is attached; and a third R’ group and a fourth R’ group which are taken together to form −Ls− which is bonded to the atom to which a third R’ group is attached and the atom to which a fourth R’ group is attached; each Lsis independently −Ls1−Ls2−Ls3−, wherein each Ls1, Ls2and Ls3is independently L; LAA1comprises an acidic or polar group (e.g., is an amino acid residue that comprises a side chain comprising an acidic or polar group); LAA2comprises an acidic or polar group (e.g., is an amino acid residue that comprises a side chain comprising an acidic or polar group); LAA3is L or an amino acid residue; LAA4comprises an optionally substituted aromatic group (e.g., is an amino acid residue that comprises a side chain comprising an optionally substituted aromatic group); LAA5comprises an optionally substituted aromatic group (e.g., is an amino acid residue that comprises a side chain comprising an optionally substituted aromatic group); LAA6comprises an optionally substituted aromatic group (e.g., is an amino acid residue that Page 854 of 884 12834799v1Attorney Docket Number: 2012675-0389 comprises a side chain comprising an optionally substituted aromatic group); RCis a peptide, a carboxyl protecting group, −LRC−R’, −O−LRC−R’ or −N(R’)−LRC−R’; each of LRNand LRCis independently L; each L is independently a covalent bond, or an optionally substituted, bivalent C1-C25aliphatic or heteroaliphatic group having 1-10 heteroatoms, wherein one or more methylene units of the group areoptionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−,−C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−; each −Cy− is independently an optionally substituted bivalent, 3-30 membered ring having 0-10 heteroatoms; each R’ is independently −L−R, −C(O)R, −CO2R, or −SO2R; and each R is independently −H, or an optionally substituted group selected from C1-30aliphatic, C1-30heteroaliphatic having 1-10 heteroatoms, C6-30aryl, C6-30arylaliphatic, C6-30arylheteroaliphatic having 1-10 heteroatoms, 5-30 membered heteroaryl having 1-10 heteroatoms, and 3-30 membered heterocyclyl having 1- 10 heteroatoms, or two R groups are optionally and independently taken together to form a covalent bond, or: two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered ring having, in addition to the atom, 0-10 heteroatoms; or two or more R groups on two or more atoms are optionally and independently taken together with their intervening atom(s) to form an optionally substituted, 3-30 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms.

28. The agent of claim 27, wherein PTBMcomprises: X1X2X3X4X5X6X7X8X9X10X11X12X13X14, wherein: each of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14is independently an amino acid residue, wherein: X2comprises a side chain comprising an acidic or a polar group; X5comprises a side chain comprising an acidic or a polar group; and each of X9, X12and X13comprises a side chain comprising an optionally substituted aromatic group.

29. The agent of any one of claims 27-28, wherein PTBMis or comprises a peptide comprising: [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17[X18]p18, wherein: each of p0, p15, p16, p17 and p18 is independently 0 or 1; each of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17and X18is independently an amino acid residue, wherein: Page 855 of 884 12834799v1Attorney Docket Number: 2012675-0389 X2comprises a side chain comprising an acidic or a polar group; X5comprises a side chain comprising an acidic or a polar group; X13comprises a side chain comprising an optionally substituted aromatic group; and two or more of X1, X3, X4, X7, X10, X11and X14are each independently an amino acid residue suitable for stapling, or are each independently stapled.

30. The agent of any one of claims 27-29, wherein PTBMcomprises one, two, three or more staples within10-20 amino acid residues; two, three or more of X0, X1, X3, X4, X7, X10, X11and X14are each independently an amino acid residue suitable for stapling, or are each independently stapled; X1and X4are connected by a staple; X0and X4are connected by a staple; X4and X11are connected by a staple; X10and X14are connected by a staple, X7and X10are connected by a staple, and / or X7and X14are connected by a staple.

31. The agent of any one of claims 27-30, wherein PTBMcomprises a N-terminal group.

32. The agent of any one of claims 27-31, wherein X1is a residue of an amino acid that comprises −CH=CH2.

33. The agent of claim 32, wherein X1is PL3.

34. The agent of any one of claims 27-33, wherein X4is a residue of an amino acid that comprises an olefin.

35. The agent of claim 34, wherein X4is B5.

36. The agent of any one of claims 27-35, wherein X11is a residue of an amino acid that comprises an olefin.

37. The agent of claim 36, wherein X11is PyrS2.

38. The agent of any one of claims 27-37, wherein X10is a residue of an amino acid that comprises an optionally substituted carboxyl group, an optionally substituted amino group, an azidyl group, an optionally substituted alkynyl group, or an optionally substituted thiol group.

39. The agent of any one of claims 27-38, wherein X14is a residue of an amino acid that comprises a carboxyl group, an amino group, an azidyl group, an alkynyl group, or a thiol group.

40. The agent of any one of claims 27-37, wherein one of X10and X14is a residue of an amino acid that comprises a carboxyl group, and the other is a residue of an amino acid that comprises an amino group, optionally wherein X10and X14are connected by a staple, wherein the staple comprises −C(O)N(R’)−.

41. The agent of any one of claims 27-40, wherein X2comprises a side chain comprising an acidic group.

42. The agent of claim 41, wherein X2is Asp.

43. The agent of any one of claims 27-42, wherein X3comprises one or two hydrophobic side chains. Page 856 of 884 12834799v1Attorney Docket Number: 2012675-0389 44. The agent of any one of claims 27-43, wherein X5comprises a side chain comprising an acidic group.

45. The agent of claim 44, wherein X5is Asp, 3COOHF, or Glu.

46. The agent of any one of claims 27-45, wherein X6comprises a side chain comprising an acidic group.

47. The agent of claim 46, wherein X6is 3COOHF, TfeGA, Asp, or Glu.

48. The agent of any one of claims 27-47, wherein X7is a hydrophobic amino acid residue, or wherein X7comprises a side chain comprising a basic group, or wherein X7comprises a side chain comprising an aromatic group.

49. The agent of any one of claims 27-48, wherein X8is a hydrophobic amino acid residue, or wherein X8comprises a side chain comprising a basic group.

50. The agent of any one of claims 27-49, wherein X9comprises a side chain which is or comprises an optionally substituted aromatic group.

51. The agent of claim 50, wherein X9is Phe, 2Thi, Tyr, 3Thi, 4FF, 4ClF, 4BrF, 3FF, 3ClF, 3BrF, 2FF, 3OMeF, 4CNF, 3CNF, 4MeF, 3MeF, BztA, 1NapA, Trp or 3F3MeF.

52. The agent of any one of claims 27-51, wherein X10comprises a side chain comprising a basic group.

53. The agent of any one of claims 27-52, wherein X12comprises a side chain which is or comprises an optionally substituted aromatic group.

54. The agent of claim 53, wherein X12is 3Thi, 2F3MeF, Phe, nLeu, 2COOHF, CypA, 2ClF, Ala, Abu, Leu, hLeu, Npg, Cpa, Nva, Cba, ChA, 2FurA, 2OMeF, 2MeF, 2BrF, 2CNF, 2NO2F, 2PyrA, 3PyrA, 4PyrA, His, 1NapA, Val, Ile, Chg, DiethA, hnLeu, OctG, 2Thi, or 2cbmF.

55. The agent any one of claims 27-54, wherein the side chain of X13comprises an optionally substituted aromatic group.

56. The agent of claim 55, wherein X13is selected from BztA, 2NapA, 34ClF, 3Thi, Phe, GlnR, 34MeF, or 2Nap.

57. The agent any one of claims 27-54, wherein X13comprises a side chain comprising a basic group.

58. The agent of any one of claims 27-57, wherein p15 is 1.

59. The agent of claim 58, wherein X15comprises a side chain comprising a basic or aromatic group.

60. The agent of any one of claims 27-59, wherein p16 is 1.

61. The agent of claim 60, wherein X16comprises a side chain comprising a basic or aromatic group.

62. The agent of any one of claims 27-61, wherein p17 is 1.

63. The agent of claim 62, wherein X17comprises a side chain comprising a basic group.

64. The agent of any one of claims 27-63, wherein p18 is 1.

65. The agent of claim 64, wherein X18comprises a side chain comprising a basic group.

66. The agent of any one of claims 27-59, wherein p16 is 0, p17 is 0 and p18 is 0.

67. The agent of any one of claims 27-66, wherein the peptide forms a structure that comprises a helix.

68. The agent of any one of claims 1-67, wherein the agent or peptide binds to beta-catenin, or wherein the peptide binds to a polypeptide whose sequence is or comprising SEQ ID NO: 2, or a fragment thereof: Page 857 of 884 12834799v1Attorney Docket Number: 2012675-0389 SVLFYAITTLHNLLLHQEGAKMAVRLAGGLQKMVALLNKTNVKFLAITTDCLQILAYGNQESKLIIL ASGGPQALVNIMRTYTYEKLLWTTSRVLKVLSVCSSNKPAIVEAGGMQALGLHLTDPSQRLVQNCL WTLRNLSDAATKQEGMEGLLGTLVQLLGSDDINVVTCAAGILSNLTCNNYKNKMMVCQVGGIEAL VRT (SEQ ID NO: 2).

69. The agent of any one of claims 1-68, wherein the agent interacts with Y306, G307, K312, R342, K345, V349, Q379, L382, W383, R386, N387, D413, N415, V416, or C419 of beta-catenin or an amino acid corresponding thereto.

70. The agent of any one of claims 68-69, wherein X2, X5, X6, X9, X12, and / or X13interact with beta- catenin.

71. An agent, wherein the agent is C1(=O)[C@]2(N(CCC2)C(CCOCCOCCOCCOCCOCc2cn([C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N Cc3ccc(cc3)- c3c(C)ncs3)C(C)(C)C)nn2)=O)CC=CCCCC2(CCCC=CCCCOC(=O)N3C[C@@]4(CC3)C(=O)N[C@]([H])( C(=O)N[C@]([H])(C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N)CCC(=O)NCCCC[C@@H](C(=O)N4)NC ([C@H](Cc3ccccc3)NC([C@H](C)NC(C(NC([C@](NC(=O)[C@@H](NC2=O)CC(=O)O)([H])Cc2cc(ccc2) C(O)=O)=O)(C)C)=O)=O)=O)Cc2c3c(sc2)cccc3)Cc2cscc2)NC([C@](NC(=O)[C@@H](N1)CC(=O)O)([H] )CC(C)(C)C)=O, C1(=O)[C@]2(N(CCC2)C(CCOCCOCCOCCOCCOCCOCCOCCOCc2cn([C@H](C(=O)N3C[C@H](O)C[ C@H]3C(=O)NCc3ccc(cc3)- c3c(C)ncs3)C(C)(C)C)nn2)=O)CC=CCCCC2(CCCC=CCCCOC(=O)N3C[C@@]4(CC3)C(=O)N[C@]([H])( C(=O)N[C@]([H])(C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N)CCC(=O)NCCCC[C@@H](C(=O)N4)NC ([C@H](Cc3ccccc3)NC([C@H](C)NC(C(NC([C@](NC(=O)[C@@H](NC2=O)CC(=O)O)([H])Cc2cc(ccc2) C(O)=O)=O)(C)C)=O)=O)=O)Cc2c3c(sc2)cccc3)Cc2cscc2)NC([C@](NC(=O)[C@@H](N1)CC(=O)O)([H] )CC(C)(C)C)=O, C1(=O)[C@]2(N(CCC2)C(C)=O)CC=CCCCC2(CCCC=CCCCOC(=O)N3C[C@@]4(CC3)C(=O)N[C@]([ H])(C(=O)N[C@]([H])(C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N)CCC(=O)NCCCC[C@@H](C(=O)N4 )NC([C@H](Cc3ccccc3)NC([C@H](C)NC(=O)[C@@H](NC([C@](NC(=O)[C@@H](NC2=O)CC(=O)O)([ H])Cc2cc(ccc2)C(O)=O)=O)CCCCNC(CCOCCOCc2cn([C@](C(N3[C@](C(=O)NCc4ccc(cc4)- C ([ )N4 O)([ cc(c3c(C)ncs3)C(C)(C)C)nn2)=O)=O)=O)Cc2c3c(sc2)cccc3)Cc2cscc2)NC([C@](NC(=O)[C@@H](N1)CC(= Page 858 of 884 12834799v1Attorney Docket Number: 2012675-0389 O)O)([H])CC(C)(C)C)=O, N(CCOCC(=O)N1[C@]2(C(=O)N[C@H](C(=O)N[C@]([H])(C(=O)NC3(CCCC=CCCCOC(=O)N4C[C@ @]5(CC4)C(=O)N[C@]([H])(C(=O)N[C@]([H])(C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N)CCC(=O)N 3= C( 1)c ccc cc -c scnc , C1(=O)[C@]2(N(CCC2)C(C)=O)CC=CCCCC2(CCCC=CCCCOC(=O)N3C[C@@]4(CC3)C(=O)N[C@]([ H])(C(=O)N[C@]([H])(C(=O)N[C@H](C(=O)N[C@H](C(=O)N)CCCCNC(CCOCCOCCOCCOCc3cn([C @H](C(=O)N5C[C@H](O)C[C@H]5C(=O)NCc5ccc(cc5)- c5c(C)ncs5)C(C)(C)C)nn3)=O)CCC(=O)NCCCC[C@@H](C(=O)N4)NC([C@H](Cc3ccccc3)NC([C@H](C )NC(C(NC([C@](NC(=O)[C@@H](NC2=O)CC(=O)O)([H])Cc2cc(ccc2)C(O)=O)=O)(C)C)=O)=O)=O)Cc2 c3c(sc2)cccc3)Cc2cscc2)NC([C@](NC(=O)[C@@H](N1)CC(=O)O)([H])CC(C)(C)C)=O, C(=O)([C@]1([H])CN(CCC1)C(C[C@H](NC(=O)[C@@H]1C[C@H](CN1C(=O)[C@H](C(C)(C)C)n1nnc( c1)C1CC1)O)c1ccc(cc1)- c1scnc1C)=O)NCC(=O)N1[C@]2(C(=O)N[C@H](C(=O)N[C@]([H])(C(=O)NC3(CCCC=CCCCOC(=O)N 4C[C@@]5(CC4)C(=O)N[C@]([H])(C(=O)N[C@]([H])(C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N)CC C(=O)NCCCC[C@@H](C(=O)N5)NC([C@H](Cc4ccccc4)NC([C@H](C)NC(C(NC([C@](NC(=O)[C@@ C= 1n C(= )N) @ C([ H])(C(=O)N[C@]([H])(C(=O)N[C@H](C(=O)N[C@H](C(=O)N)CCCCNC(COCCOCCOCCNC(C[C@H]( NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)n3nnc(c3)C3CC3)O)c3ccc(cc3)- c3scnc3C)=O)=O)CCC(=O)NCCCC[C@@H](C(=O)N4)NC([C@H](Cc3ccccc3)NC([C@H](C)NC(C(NC([ C@](NC(=O)[C@@H](NC2=O)CC(=O)O)([H])Cc2cc(ccc2)C(O)=O)=O)(C)C)=O)=O)=O)Cc2c3c(sc2)cccc 3)Cc2cscc2)NC([C@](NC(=O)[C@@H](N1)CC(=O)O)([H])CC(C)(C)C)=O, C1(=O)[C@]2(N(CCC2)C(C)=O)CC=CCCCC2(CCCC=CCCCOC(=O)N3C[C@@]4(CC3)C(=O)N[C@]([ H])(C(=O)N[C@]([H])(C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N)CCC(=O)NCCCC[C@@H](C(=O)N4 Cc12834799v1Attorney Docket Number: 2012675-0389 2cc(ccc2)C(O)=O)=O)CN(CC3)C(COCc2cn([C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)NCc3ccc(cc3)- c3c(C)ncs3)C(C)(C)C)nn2)=O)=O)=O)=O)Cc2c3c(sc2)cccc3)Cc2cscc2)NC([C@](NC(=O)[C@@H](N1)C C(=O)O)([H])CC(C)(C)C)=O, C1(=O)[C@]2(N(CCC2)C(C)=O)CC=CCCCC2(CCCC=CCCCOC(=O)N3C[C@@]4(CC3)C(=O)N[C@]([ H])(C(=O)N[C@]([H])(C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N)CCC(=O)NCCCC[C@@H](C(=O)N4 Cc =O CC(=O)O)([H])CC(C)(C)C)=O, O=C(N1C[C@]2(C(N[C@H](C(N[C@@H](CC3=CSC4=C3C=CC=C4)C(N[C@H](C(N[C@@H](C)C(N)= O)=O)CCC(NCCCC[C@@H](C(N2)=O)NC([C@@H](NC([C@@H](NC(C(C)(C)NC([C@@H](NC([C@ @H](N5)CC(O)=O)=O)CC6=CC=CC(C(O)=O)=C6)=O)=O)C)=O)CC7=CC=CC=C7)=O)=O)=O)=O)CC8= CSC=C8)=O)CC1)OCCCC=CCCCC9(NC([C@H](CCCCNC(CCOCCOCCOCC%10=CN([C@H](C(N%11 [C@@H](C[C@H](C%11)O)C(NCC%12=CC=C(C=C%12)C%13=C(C)N=CS%13)=O)=O)C(C)(C)C)N=N %10)=O)NC([C@@H](NC([C@]%14(N(C(C)=O)CCC%14)CC=CCCC9)=O)CC(O)=O)=O)=O)C5=O, or O=C(N1C[C@]2(C(N[C@H](C(N[C@@H](CC3=CSC4=C3C=CC=C4)C(N[C@H](C(N[C@@H](C)C(N)= O)=O)CCC(NCCCC[C@@H](C(N2)=O)NC([C@@H](NC([C@H](CCNC(CCCNC(C[C@H](NC([C@H]5 N(C[C@@H](C5)O)C([C@H](C(C)(C)C)N6C=C(N=N6)C7CC7)=O)=O)C8=CC=C(C=C8)C9=C(N=CS9) C)=O)=O)NC(C(C)(C)NC([C@@H](NC([C@@H](N%10)CC(O)=O)=O)CC%11=CC=CC(C(O)=O)=C%1 1)=O)=O)=O)CC%12=CC=CC=C%12)=O)=O)=O)=O)CC%13=CSC=C%13)=O)CC1)OCCCC=CCCCC%1 4(NC([C@@H](NC([C@@H](NC([C@]%15(N(C(C)=O)CCC%15)CC=CCCC%14)=O)CC(O)=O)=O)CC( C)(C)C)=O)C%10=O, or a salt thereof.

72. The agent of any one of the preceding claims, wherein a double bond of a staple bonded to the first stapled amino acid that is bonded to a staple with a double bond, counting from the N-terminus, is E.

73. The agent of any one of claims 1-71, wherein a double bond of a staple bonded to the first stapled amino acid that is bonded to a staple with a double bond, counting from the N-terminus, is Z.

74. The agent of any one of claims 1-73, wherein a double bond of a staple bonded to the first stapled amino acid that is bonded to a staple with a double bond, counting from the C-terminus, is E.

75. The agent of any one of claims 1-73, wherein a double bond of a staple bonded to the first stapled amino acid that is bonded to a staple with a double bond, counting from the C-terminus, is Z.

76. The agent of any one of claims 1-75, wherein a double bond of a (i, i+7) staple is E.

77. The agent of any one of claims 1-76, wherein a double bond of a (i, i+7) staple is Z.

78. The agent of any one of claims 1-77, wherein a double bond of a (i, i+2), (i, i+3) or (i, i+4) staple is E. Page 860 of 884 12834799v1Attorney Docket Number: 2012675-0389 79. The agent of any one of claims 1-78, wherein a double bond of a (i, i+2), (i, i+3) or (i, i+4) staple is Z.

80. The agent of any one of claims 1-79, wherein a double bond of a staple bonded to the first amino acid from the N-terminus is Z.

81. The agent of any one of claims 1-80, wherein a double bond of a staple bonded to the 11th amino acid from the N-terminus is E.

82. The agent of any one of claims 1-81, wherein a double bond of a staple bonded to the 11th amino acid from the N-terminus is Z.

83. The agent of any one of claims 1-82, wherein a carbon atom bonded to two staples (e.g., in B5) is of R configuration.

84. The agent of any one of any claims 1-83, wherein a carbon atom bonded to two staples (e.g., in B5) is of S configuration.

85. The agent of any one of claims 2-26, wherein TBM is −[PTBM], wherein PTBMis of structure SP-1-1, SP-1-2, SP-1-3, SP-1-4, SP-1-5, SP-1-6, SP-1-7, SP-1-8, SP-2-1, SP-2-2, SP-2-3, SP-2-4, SP-2-5, SP-2-6, SP-2-7, SP-2-8, SP-3-1, SP-3-2, SP-4-1, SP-4-2, SP-4-3, SP-4-4, SP-4-5, SP-4-6, SP-4-7, SP-4-8, SP-5-1, SP-5-2, SP-5-3, SP-5-4, SP-5-5, SP-5-6, SP-5-7, SP-5-8, SP-6, SP-7-1, SP-7-2, SP-7-3, SP-7-4, SP-7-5, SP- 7-6, SP-7-7, SP-7-8, SP-8-1, SP-8-2, SP-8-3, SP-8-4, SP-8-5, SP-8-6, SP-8-7, SP-8-8, SP-9-1, SP-9-2, SP-9- 3, SP-9-4, SP-9-5, SP-9-6, SP-9-7, SP-9-8, SP-10-1, SP-10-2, SP-10-3, SP-10-4, SP-10-5, SP-10-6, SP-10-7, SP-10-8, SP-11-1, SP-11-2, SP-11-3, SP-11-4, SP-11-5, SP-11-6, SP-11-7, SP-11-8, SP-12-1, SP-12-2, SP- 12-3, SP-12-4, SP-12-5, SP-12-6, SP-12-7, SP-12-8, SP-13-1, SP-13-2, SP-13-3, SP-13-4, SP-13-5, SP-13-6, SP-13-7, SP-13-8, SP-14-1, SP-14-2, SP-14-3, SP-14-4, SP-14-5, SP-14-6, SP-14-7, SP-14-8, SP-15-1, SP- 15-2, SP-15-3, SP-15-4, SP-15-5, SP-15-6, SP-15-7, SP-15-8, or a salt thereof. Page 861 of 884 12834799v1Attorney Docket Number: 2012675-0389 86. The agent of any one of claims 1-26, wherein TBM is −[PTBM], wherein PTBMis NH2OSHN Of. wherein PTBMisNH2OS.Page 862 of 884 12834799v1Attorney Docket Number: 2012675-0389 88. The agent of any one of claims 1-26, wherein TBM is −[PTBM], wherein PTBMis NH2OSof. wherein PTBMisNH2OSof.. , nected to X1, X3, X7, X8, X10, X14, X15, X16, X17, X18or the N-terminal X. Page 863 of 884 12834799v1Attorney Docket Number: 2012675-0389 91. The agent of any one of claims 1-26, wherein TBM is NH2OSSHN OOH,Page 864 of 884 12834799v1Attorney Docket Number: 2012675-0389 H N NH2NH2 OSH2H2Page 865 of 884 12834799v1Attorney Docket Number: 2012675-0389 NH2O HN O 2H,Page 866 of 884 12834799v1Attorney Docket Number: 2012675-0389 NH2 H2N OO S HO NH HN O,Page 867 of 884 12834799v1Attorney Docket Number: 2012675-0389 NH2O S HN OO ,Page 868 of 884 12834799v1Attorney Docket Number: 2012675-0389 NH2NH2O S O S HN OOHN OO S HPage 869 of 884 12834799v1Attorney Docket Number: 2012675-0389 H N S NH2H2N OSO O H O HN O OHNNH HN H O O NHNOO S NH HHNO S NH HN N HN O , OH ,12834799v1Attorney Docket Number: 2012675-0389 NH2OSHNO OH ,Page 871 of 884 12834799v1Attorney Docket Number: 2012675-0389 NH2HON HN H H N S OOHO OOHNOO HO OH O , Page 872 of 884 12834799v1Attorney Docket Number: 2012675-0389 S OH,Page 873 of 884 12834799v1Attorney Docket Number: 2012675-0389 NH2OS,Page 874 of 884 12834799v1Attorney Docket Number: 2012675-0389 NH2OSHN OOH ,Page 875 of 884 12834799v1Attorney Docket Number: 2012675-0389 N N OH,Page 876 of 884 12834799v1Attorney Docket Number: 2012675-0389 S O OH,Page 877 of 884 12834799v1Attorney Docket Number: 2012675-0389 S O OH,Page 878 of 884 12834799v1Attorney Docket Number: 2012675-0389 O OH N NH ndPage 879 of 884 12834799v1Attorney Docket Number: 2012675-0389 NH2OSsalty interacting with a second polypeptide, wherein the agent is capable of binding to the first and the second polypeptide simultaneously; and optionally: wherein the agent binds beta-catenin through amino acid residues and an E3 ligase through the E3 ligase ligand moiety; and wherein the peptide binds to beta-catenin and interacts with one or more residues that are or correspond to at least two, or at least three, or at least four, or at least five, or at least six, or at least seven, or at least eight or at least nine, or at least ten, or at least eleven, or at least twelve, or at least thirteen, or at least fourteen, or at least fifteen, or at least sixteen, or at least seventeen, or at least eighteen, or at least nineteen, or at least twenty of the following amino acid residues in SEQ ID NO: 1 at the indicated positions: A305, Y306, G307, N308, Q309, K312, R342, K345, V346, V349, Q375, R376, Q379, N380, L382, W383, R386, N387, D413, N415, V416, T418, and C419.

94. A pharmaceutical composition, comprising or delivering an agent of any one of the preceding claims, and a pharmaceutically acceptable carrier.

95. A method for preparing an agent or composition of any one of the preceding claims, comprising: contacting a TBM reactive agent comprising TBM and a TBM reactive group with a LBM reactive agent comprising LBM and a LBM reactive group; Page 880 of 884 12834799v1Attorney Docket Number: 2012675-0389 wherein the TBM reactive group reacts with a LBM reactive group.

96. A method for modulating beta-catenin interaction with a partner in a system, comprising contacting beta-catenin with an agent or composition of any one of the preceding claims; or a method for modulating beta-catenin interaction with a partner in a system, comprising administering or delivering to the system an agent or composition of any one of the preceding claims, optionally wherein the partner is TCF7, LEF1, TCF7L1, TCF7L2, Axin1, Axin2, or APC; a method for modulating a TCF-beta-catenin interaction in a system, comprising contacting beta- catenin with an agent or composition of any one of the preceding claims; or a method for modulating a TCF-beta-catenin interaction in a system, comprising administering or delivering to the system an agent or composition of any one of the preceding claims; or a method for inhibiting beta-catenin dependent cell proliferation in a system, comprising administering or delivering to the system an agent or composition of any one of the preceding claims; or a method for increasing ubiquitination of beta-catenin polypeptide in a system, comprising administering or delivering to the system an agent or composition of any one of the preceding claims; or a method for reducing beta-catenin polypeptide level in a system, comprising administering or delivering to the system an agent or composition of any one of the preceding claims; or a method for modulating WNT / beta-catenin pathway in a system, comprising administering or delivering to the system an agent or composition of any one of the preceding claims, wherein expression of a nucleic acid is modulated; or a method for modulating nucleic acid expression in a system, comprising administering or delivering to the system an agent or composition of any one of the preceding claims; or a method for reducing AXIN2 expression in a system, comprising administering or delivering to the system an agent or composition of any one of the preceding claims; or a method for reducing MYCN expression in a system, comprising administering or delivering to the system an agent or composition of any one of the preceding claims; or a method for increasing CXCL12 expression in a system, comprising administering or delivering to the system an agent or composition of any one of the preceding claims.

97. The method of claim 96, wherein a system is or comprises a sample; or a system is or comprises a cell, tissue or organ; or a system is or comprises cancer cells; or a system is or comprises colorectal cancer cells; or a system is or comprises COLO320DM cells; or a system is or comprises a tumor; or a system is a subject. Page 881 of 884 12834799v1Attorney Docket Number: 2012675-0389 98. A method for treating or preventing a condition, disorder or disease associated with beta-catenin in a subject, comprising administering or delivering to the subject an effective amount of an agent or composition of any one of the preceding claims; or a method for treating or preventing a condition, disorder or disease associated with TCF-beta-catenin interaction in a subject, comprising administering or delivering to the subject an effective amount of an agent or composition of any one of the preceding claims; or a method for treating or preventing a condition, disorder or disease in a subject, comprising administering or delivering to the subject an effective amount of an agent or composition of any one of the preceding claims, optionally wherein the condition, disorder or disease is associated with or characterized by deregulation of beta-catenin.

99. The method of claim 98, wherein the condition, disorder or disease is cancer, optionally wherein: the condition, disorder or disease is colorectal cancer, wherein the colorectal cancer optionally has an APC mutation, wherein the APC mutation is optionally a RAS mutation or a TP53 mutation; or the condition, disorder or disease is hepatocellular cancer; and optionally wherein the subject has one or more beta-catenin mutations in cancer cells, wherein the beta-catenin mutation is optionally D32V, D32H, S45F, or S37C; and optionally wherein the subject has another mutation in cancer cells, optionally wherein the subject has a MSH6 mutation in cancer cells or a MSI-H mutation in cancer cells.

100. The method of any one of claims 96-99, comprising administering or delivering to a subject a second therapeutic agent or a second therapy.

101. An agent of any one of claims 1-93 or the composition of claim 94 for treating or preventing a condition, disorder, or disease optionally wherein the condition, disorder or disease is cancer, optionally wherein: the condition, disorder or disease is colorectal cancer, wherein the colorectal cancer optionally has an APC mutation, wherein the APC mutation is optionally a RAS mutation or a TP53 mutation; or the condition, disorder or disease is hepatocellular cancer; and optionally wherein the subject has one or more beta-catenin mutations in cancer cells, wherein the beta-catenin mutation is optionally D32V, D32H, S45F, or S37C; and optionally wherein the subject has another mutation in cancer cells, optionally wherein the subject has a MSH6 mutation in cancer cells or a MSI-H mutation in cancer cells.

102. An agent of any one of claims 1-93 or the composition of claim 94 for a method of any one of claims 96-100.

103. An agent of any one of claims 1-93 or the composition of claim 94 for manufacturing a medicament for treating or preventing a condition, disease, or disorder, optionally wherein the condition, disorder or disease is cancer, optionally wherein: the condition, disorder or disease is colorectal cancer, wherein the colorectal cancer optionally has an Page 882 of 884 12834799v1Attorney Docket Number: 2012675-0389 APC mutation, wherein the APC mutation is optionally a RAS mutation or a TP53 mutation; or the condition, disorder or disease is hepatocellular cancer; and optionally wherein the subject has one or more beta-catenin mutations in cancer cells, wherein the beta-catenin mutation is optionally D32V, D32H, S45F, or S37C; and optionally wherein the subject has another mutation in cancer cells, optionally wherein the subject has a MSH6 mutation in cancer cells or a MSI-H mutation in cancer cells.

104. An agent of any one of claims 1-93 or the composition of claim 94 for manufacturing a medicament for a method of any one of claims 96-100.

105. Use of an agent of any one of claims 1-93 or the composition of claim 94 for treating or preventing a condition, disorder, or disease optionally wherein the condition, disorder or disease is cancer, optionally wherein: the condition, disorder or disease is colorectal cancer, wherein the colorectal cancer optionally has an APC mutation, wherein the APC mutation is optionally a RAS mutation or a TP53 mutation; or the condition, disorder or disease is hepatocellular cancer; and optionally wherein the subject has one or more beta-catenin mutations in cancer cells, wherein the beta-catenin mutation is optionally D32V, D32H, S45F, or S37C; and optionally wherein the subject has another mutation in cancer cells, optionally wherein the subject has a MSH6 mutation in cancer cells or a MSI-H mutation in cancer cells.

106. Use of an agent of any one of claims 1-93 or the composition of claim 94 for a method of any one of claims 96-100.

107. Use of an agent of any one of claims 1-93 or the composition of claim 94 for manufacturing a medicament for treating or preventing a condition, disease, or disorder, optionally wherein the condition, disorder or disease is cancer, optionally wherein: the condition, disorder or disease is colorectal cancer, wherein the colorectal cancer optionally has an APC mutation, wherein the APC mutation is optionally a RAS mutation or a TP53 mutation; or the condition, disorder or disease is hepatocellular cancer; and optionally wherein the subject has one or more beta-catenin mutations in cancer cells, wherein the beta-catenin mutation is optionally D32V, D32H, S45F, or S37C; and optionally wherein the subject has another mutation in cancer cells, optionally wherein the subject has a MSH6 mutation in cancer cells or a MSI-H mutation in cancer cells.

108. Use of an agent of any one of claims 1-93 or the composition of claim 94 for manufacturing a medicament for a method of any one of claims 96-100.

109. An agent, compound, method, use, or composition of any one of Embodiments 1-756. Page 883 of 884 12834799v1

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