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 functions. In some embodiments, the present disclosure provides technologies for preventing and / or treating conditions, disorders or diseases associated with beta-catenin. In some embodiments, the present disclosure provides designed amino acids and agents which can provide improved properties and / or activities.

Description

STAPLED PEPTIDES AND METHODS THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No. 63 / 433,003, filed December 15, 2022, the entirety of which is incorporated herein by 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, provided technologies are useful for treating various conditions, disorders or diseases including cancer. In some embodiments, provided technologies are useful for treating colorectal cancer. In some embodiments, provided technologies are useful for treating cancer expressing high levels of Myc. In some embodiments, provided technologies reduce Myc expression levels for extended periods of time as described herein.

[0004] In some embodiments, the present disclosure provides agents, e.g., stapled peptides that comprise multiple staples. In some embodiments, the present disclosure provides agents, e.g., stapled peptides that comprise three or more staples. In some embodiments, the present disclosure provides agents, e.g., stapled peptides that comprise three or more 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., stapled peptides that comprise three or more staples within 11 consecutive amino acid residues. In some embodiments, the present disclosure provides agents, e.g., 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., 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., stapled peptides demonstrate various desired properties and / or activities. In some embodiments, provided agents, e.g., 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.).

[0005] In some embodiments, provided technologies comprise designed structural features, e.g., novel amino acid residues, that can provide significantly improved properties and / or activities compared to comparable reference technologies that do not contain such designed structural features. In some embodiments, the present disclosure provides designed amino acids as described herein, whose incorporation into peptide agents, including stapled peptides, can provide significantly improved properties and / or activities such as improved lipophilicity and / or delivery into cells compared to reference amino acids (e.g., Asp). In some embodiments, the present disclosure provides technologies including peptides comprising such designed amino acid residues. In some embodiments, the present disclosure provides stapled peptides comprise such designed amino acid residues.

[0006] 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., 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 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, K345and W383 of SEQ ID NO: 1.

[0007] As demonstrated herein, provided technologies can modulate one or more biological processes associated with beta-catenin. In some embodiments, provided agents, e.g., 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. In some embodiments, provided technologies are usefully for promoting and / or enhancing immune activities, e.g., anti-tumor adaptive immunity.

[0008] 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. In some embodiments, a condition, disorder or disease is colorectal cancer. In some embodiments, a subject has one or more mutations, e.g., as described in a model herein. In some embodiments, a cancer comprises overexpression of Myc.

[0009] In some embodiments, an agent, e.g., a staple peptide, 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. In some embodiments, a pharmaceutical composition further comprises a lipid. As demonstrated herein, in some embodiments, a suitable lipid can promote delivery / activities. In some embodiments, an agent is or comprises a peptide. In some embodiments, an agent is or comprises a stapled peptides. In some embodiments, provided agents that can bind beta-catenin comprise one or more designed amino acid residues. In some embodiments, the presentdisclosure provides a pharmaceutical composition comprising an effective amount of an agent, e.g., a stapled peptide, wherein when the composition is administered to a model as described herein, a result as described herein (e.g., reduction of tumor size, inhibition of tumor growth, etc.) is observed. In some embodiments, the present disclosure provides a pharmaceutical composition comprising an effective amount of an agent, e.g., a stapled peptide, wherein when the composition is administered to a system or a subject, Myc expression is reduced as described herein. In some embodiments, provided technologies e.g., agents, compositions, etc., are capable of reducing level of a Myc transcript. In some embodiments, provided technologies are capable of reducing level of a Myc polypeptide. In some embodiments, provided technologies are capable of reducing level of a c-Myc transcript. In some embodiments, provided technologies are capable of reducing level of a c-Myc polypeptide. In some embodiments, provided technologies are capable of reducing cell proliferation, e.g., proliferation of colorectal cancer cells. In some embodiments, provided technologies are capable of reducing tumor growth, e.g., of colorectal tumors, in subjects, PDX models, etc. In some embodiments, provided technologies are capable of shrinking tumor sizes, e.g., of colorectal tumors, in subjects, PDX models, etc. In some embodiments, cancer cells and tumors comprise mutations as described herein, e.g., APC mutations in colorectal cancer cells and tumors. In some embodiments, cancer cells and tumors contain high levels of Myc expression. In some embodiments, cancer cells and tumors contain high levels of c-Myc transcripts and / or polypeptides.

[0010] In some embodiments, the present disclosure provides agents that 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 MSEDKPQDYKKRLSVELTSSLFRTEPMAWNETADLGLDIGAQGEPLGYRQDDPSYRSFHSGGYGQD ALGMDPMMEHEMGGHHPGADYPVDGLPDLGHAQDLMDGLPPGDSNQLAWFDTDL (SEQ ID NO: 1).

[0011] 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 an ICAT 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 in accordance with the present disclosure.

[0012] In some embodiments, the provided technology provides an agent, e.g., a stapled peptide, that comprises multiple, e.g., two, three, 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 three or more staples within 10 consecutive amino acid residues. In some embodiments, there are three or more staples within 11consecutive 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.

[0013] In some embodiments, a first staple in an agent, e.g., a staple peptide, are 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 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.

[0014] 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.

[0015] In some embodiments, an agent, e.g., 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. For example, in compound I-1, a (i, i+3) staple is bonded to amino acid residues at positions 1 and 4, and a (i, i+7) staple is bonded to amino acid residues at positions 4 and 11, and the two staples are both bonded to the alpha carbon of the amino acid residue at position 4. 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 twostaples. 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.

[0016] In some embodiments, a provided agent, e.g., a peptide agent such as a stapled peptide agent, 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 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 peptidemotif, 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 peptide motif is or comprises an agent described in a Table herein (e.g., I-xxxx wherein xxxx is a number (e.g., I-1, I-10, I-100, I-1000, etc.)). 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 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 aromaticgroup 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.

[0017] In some embodiments, the present disclosure provides an agent having 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 each variable is independently as described herein.

[0018] In some embodiments, the present disclosure provides an agent which is or comprises a peptide comprising: [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17, wherein: each of p0, p15, p16 and p17 is independently 0 or 1; each of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, and X17is independently an amino acid residue.

[0019] In some embodiments, the present disclosure provides an agent which is or comprises a peptide comprising: [X]pX1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17[X]p’, wherein: each of p15, p16 and p17 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, and X17is independently an amino acid residue.

[0020] In some embodiments, an agent is RN−[X]pX1X2X3X4X5X6X7X8X9X10X11X12X13[X14]p14[X15]p15[X16]p16[X17]p17[X]p’−RC, wherein each variable is independently as described herein.

[0021] In some embodiments, an agent 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.

[0022] 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.

[0023] In some embodiments, the present disclosure provides an agent, wherein the agent is orcomprises a peptide comprising: [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17, wherein: each of p0, p15, p16 and p17 is independently 0 or 1; each of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, and X17is 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.

[0024] In some embodiments, the present disclosure provides an agent, wherein the agent is or comprises a peptide comprising: [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17, wherein: each of p0, p15, p16 and p17 is independently 0 or 1; each of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, and X17is 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.

[0025] 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. 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 X4are 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 connectingX1and 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.

[0026] In some embodiments, the present disclosure provides agents that bind to a polypeptide comprising or consisting of residues 305-419 of SEQ ID NO: 1 as described herein. In some embodiments, an agent, e.g., a peptide, has a molecular mass of no more than about 5000 Daltons. In some embodiments, it is no more than 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.

[0027] 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).

[0028] 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 a pharmaceutically acceptable salt form. In some embodiments, a provided 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.

[0029] In some embodiments, the present disclosure provides methods for modulating a 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 property, activity and / or function of beta-catenin in a system comprising or expressing beta-catenin, comprising administering or delivering to a system an effective amount of a provided agent. In some embodiments, an activity or function of beta- catenin is inhibited or reduced. In some embodiments, a property, activity and / or function is associated with beta-catenin / TCF interaction.

[0030] 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 orexpressing beta-catenin and TCF, comprising administering or delivering to the system an effective amount a provided agent. In some embodiments, interactions between beta-catenin and TCF is reduced. In some embodiments, interactions between beta-catenin and TCF is inhibited.

[0031] 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 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.

[0032] 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, e.g., colorectal cancer cells. In some embodiments, a system comprises a mutation as described herein. In some embodiments, a system overexpresses Myc.

[0033] 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, survivals 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 with beta-catenin interaction with TCF. In some embodiments, a condition, disorder or disease is associated with Myc overexpression. 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. Insome 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.

[0034] 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.

[0035] 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 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.

[0036] Further description of certain embodiments of provided technologies is presented below. BRIEF DESCRIPTION OF THE DRAWING

[0037] Figure 1. Provided technologies can inhibit beta-catenin driven gene transcription selectively in cells expressing beta-catenin. Stapled peptides inhibited endogenous gene expression in wild HAP1 isogeniccell but not in CTNNB1 knockout (KO) cells. (A): beta-catenin levels. CHIR: CHIR99021, which can activate beta-catenin pathway and increase AXIN2 and SP5 expression. (B): SP5 expression (24h). (C): AXIN2 expression (24h). For each group, from left to right, DMSO (“0” and “0”), Peptide A (1 and 5 uM), I-66 (1 and 5 uM) and I-470 (1 and 5 uM). Expression assessed after 24 hour treatment.

[0038] Figure 2. Provided technologies can reduce nuclear beta-catenin levels. Results for total beta- catenin in nuclear fraction (24 h) are shown as examples.

[0039] Figure 3. Provided technologies can inhibit cell proliferation, modulate transcription and / or induce cell cycle arrest. (A): Provided technologies can reduce cell proliferation. (B) and (C): Provided technologies can modulate gene expression. (B): AXIN 24 hr. (C): CXCL1224 hr. (D): Provided technologies can induce cell cycle arrest. For left to right: Peptide A (1, 5 and 10 uM), I-66 (1, 5 and 10 uM), I-470 (1, 5 and 10 uM) and DMSO.

[0040] Figure 4. Provided technologies can provide robust, dose-dependent anti-tumor effects in vivo. Both dose levels assessed provided robust reduction of tumor sizes, and the higher dose levels provided greater reductions. COLO320DM cells (colon cancer, mutations: APC, TP53) were utilized for the presented data. Top line is for vehicle treatment, the middle line is for I-66, 30 mg / kg, Q4D, and the bottom line is for I-66, 75 mg / kg, Q4D.

[0041] Figure 5. Provided technologies can provide sustained tumor exposure, suitable pharmacokinetic profiles and broad tissue distribution. (A): Sustained COLO320DM xenograft tumor exposure after a single i.p. injection of I-66 at 50 mg / kg was shown as an example. Dotted line indicates in vitro proliferation IC50(0.7 uM). (B): Mouse plasma pharmacokinetics. Data presented are I-66 plasma concentration (ng / mL) over time as examples. (C): Tissue distribution observed for I-66 in one assessment. Mouse single dose IP, 50 mg / kg. For each sample, the left column is 24 h data and the right is 96 h data.

[0042] Figure 6.1H NMR of a preparation of I-66 prepared as described in Example 3 (DMSO-d6, 373K).

[0043] Figure 7. Integration of peaks in a1H NMR spectrum of a preparation of I-66 prepared as described in Example 3 (DMSO-d6, 373K). Those skilled in the art appreciate that integration may be further adjusted and / or optimized.

[0044] Figure 8. Provided technologies can provide robust anti-tumor effects in vivo in multiple tumor models. (A): Certain data from a colorectal (CRC) patient derived xenograft PDX) tumor model. (B): Certain data from another colorectal (CRC) patient derived xenograft PDX) tumor model.

[0045] Figure 9.1H NMR of a preparation of I-66 as an example. Solvent: methanol-d4. About 10 mg / 750 uL. Temperature: 298 K. Number of scans: 8. Receiver gain: 30.1. Relaxation Delay: 2.5000. Acquisition Time: 1.5139. Spectrometer Frequency: 900.30 MHz. Spectra Width: 10822.5. Lowest Frequency: -927.2. Acquired Size: 16384. Spectral Size: 65536. Digital Resolution: 0.17.

[0046] Figure 10. A region of1H NMR of I-66 as an example. Top: 900 MHz1H of a preparation of I- 66 in methanol-d4, 298 K, about 10 mg / 750 uL. Bottom: 500 MHz1H of a preparation of I-66 in methanol-d4, 298 K, about 10 mg / 500 uL. As shown here, the top spectra can provide improved resolution for various peaks.

[0047] Figure 11. A region of1H NMR of I-66 as an example. Top: 900 MHz1H of a preparation of I- 66 in methanol-d4, 298 K, about 10 mg / 750 uL. Bottom: 500 MHz1H of a preparation of I-66 in methanol- d4, 298 K, about 10 mg / 500 uL. As shown here, the top spectra can provide improved resolution for various peaks; certain NH peaks at about 7.7ppm that were observed in the 500 MHz data were absent in the 900 MHz data. As those skilled in the art appreciate, NH peaks may change depending on sample environments.

[0048] Figure 12.13C NMR of a preparation of I-66 as an example. Solvent: methanol-d4. About 10 mg / 750 uL. Temperature: 298 K. Number of scans: 8108. Receiver gain: 177.2. Relaxation Delay: 1.5000. Acquisition Time: 0.3277. Spectrometer Frequency: 226.40 MHz. Spectra Width: 50000.0. Lowest Frequency: -911.8. Acquired Size: 16384. Spectral Size: 65536. Digital Resolution: 0.76.

[0049] Figure 13. COSY of a preparation of I-66 as an example. Solvent: methanol-d4. About 10 mg / 750 uL. Temperature: 298 K. Number of scans: 4. Receiver gain: 30.1. Relaxation Delay: 2.0000. Acquisition Time: 0.2272. Spectrometer Frequency: (900.30, 900.30). Spectra Width: (9014.4, 9009.0). Lowest Frequency: (-22.7, -23.3). Nucleus: (1H,1H). Acquired Size: (2048, 1024). Spectral Size: (2048, 1024). Digital Resolution: (4.40, 8.80).

[0050] Figure 14.1H-13C HSQC of a preparation of I-66 as an example. Solvent: methanol-d4. About 10 mg / 750 uL. Temperature: 298 K. Number of scans: 8. Receiver gain: 177.2. Relaxation Delay: 1.5000. Acquisition Time: 0.1137. Spectrometer Frequency: (900.30, 226.40). Spectra Width: (9009.0, 34013.6). Lowest Frequency: (-22.0, 288.5). Nucleus: (1H,13C). Acquired Size: (1024, 512). Spectral Size: (1024, 1024). Digital Resolution: (8.80, 33.22).

[0051] Figure 15.1H-13C HMBC of a preparation of I-66 as an example. Solvent: methanol-d4. About 10 mg / 750 uL. Temperature: 298 K.

[0052] Figure 16.1H-1H TOCSY of a preparation of I-66 as an example. Solvent: methanol-d4. About 10 mg / 750 uL. Temperature: 298 K. Number of scans: 8. Receiver gain: 57.7. Relaxation Delay: 2.0000. Acquisition Time: 0.2272. Spectrometer Frequency: (900.30, 900.30). Spectra Width: (9014.4, 9009.0). Lowest Frequency: (-21.8, -23.3). Acquired Size: (2048, 800). Spectral Size: (2048, 1024). Digital Resolution: (4.40, 8.80).

[0053] Figure 17.1H-1H NOESY of a preparation of I-66 as an example. Solvent: methanol-d4. About 10 mg / 750 uL. Temperature: 298 K. Number of scans: 8. Receiver gain: 57.7. Relaxation Delay: 2.0000. Acquisition Time: 0.2272. Spectrometer Frequency: (900.30, 900.30). Spectra Width: (9014.4, 9009.0). Lowest Frequency: (-5.7, -3.0). Acquired Size: (2048, 1024). Spectral Size: (2048, 1024). Digital Resolution: (4.40, 8.80).

[0054] Figure 18. Expansion of1H-1H NOESY of a preparation of I-66 as an example. Solvent: methanol-d4. About 10 mg / 750 uL. Temperature: 298 K. Number of scans: 8. Receiver gain: 57.7. Relaxation Delay: 2.0000. Acquisition Time: 0.2272. Spectrometer Frequency: (900.30, 900.30). SpectraWidth: (9014.4, 9009.0). Lowest Frequency: (-5.7, -3.0). Acquired Size: (2048, 1024). Spectral Size: (2048, 1024). Digital Resolution: (4.40, 8.80). As shown herein, NOE peak between the olefin protons of the PL3- B5 staple (111 and 112) was observed. In some embodiments, this peak was stronger than the NOE peak between neighboring aromatic protons of 3Thi (20 and 21), and / or of the p and m protons in the phenyl group of Phe (48 and 47 / 49).

[0055] Figure 19. Provided technologies can reduce beta-catenin polypeptide levels while increasing CTNNB1 mRNA levels. CRC PDX tumor (PIK3CA H1047R). Administration: IP. For each graph from left to right: protein and mRNA single-dose: vehicle (10 mg / mL arginine / 6% PEG400 phosphate), I-6660 mg / kg 2 days post-dose, I-6660 mg / kg 7 days post-dose; protein and mRNA 2 doses (Q4D): vehicle, I-47020 mg / kg 2 days post last dose, I-6620 mg / kg 2 days post last dose, I-6660 mg / kg 2 days post last dose, I-6660 mg / kg 7 days post last dose; protein and mRNA 3 doses (Q4D): vehicle, I-47020 mg / kg 2 days post last dose, I-6620 mg / kg 2 days post last dose, I-6660 mg / kg 2 days post last dose, I-6660 mg / kg 7 days post last dose. ns: not significant; *, **, ***, and **** reflect different significance levels.

[0056] Figure 20. Provided technologies can reduce polypeptide and mRNA levels of c- and N-Myc. CRC PDX tumor (PIK3CA H1047R). Administration: IP. (A): protein (western blot). For each graph from left to right: single-dose: vehicle (10 mg / mL arginine / 6% PEG400 phosphate), I-6660 mg / kg 2 days post- dose, I-6660 mg / kg 7 days post-dose; 2 doses (Q4D): vehicle, I-47020 mg / kg 2 days post last dose, I-6620 mg / kg 2 days post last dose, I-6660 mg / kg 2 days post last dose, I-6660 mg / kg 7 days post last dose; 3 doses (Q4D): vehicle, I-47020 mg / kg 2 days post last dose, I-6620 mg / kg 2 days post last dose, I-6660 mg / kg 2 days post last dose, I-6660 mg / kg 7 days post last dose. (B): mRNA (RNAseq). For each graph from left to right: vehicle, I-6660 mg / kg 2 days post last dose, I-6660 mg / kg 7 days post last dose. ns: not significant; *, **, ***, and **** reflect different significance levels.

[0057] Figure 21. Provided technologies can modulate transcripts and polypeptide levels. (A): Provided technologies can reduce Axin2 polypeptide and mRNA levels. CRC PDX tumor (PIK3CA H1047R). Administration: IP. For each graph from left to right: protein and mRNA single-dose: vehicle (10 mg / mL arginine / 6% PEG400 phosphate), I-6660 mg / kg 2 days post-dose, I-6660 mg / kg 7 days post-dose; protein and mRNA 2 doses (Q4D): vehicle, I-47020 mg / kg 2 days post last dose, I-6620 mg / kg 2 days post last dose, I-6660 mg / kg 2 days post last dose, I-6660 mg / kg 7 days post last dose; protein and mRNA 3 doses (Q4D): vehicle, I-47020 mg / kg 2 days post last dose, I-6620 mg / kg 2 days post last dose, I-6660 mg / kg 2 days post last dose, I-6660 mg / kg 7 days post last dose. ns: not significant; *, **, ***, and **** reflect different significance levels. (B)-(F): Provided technologies can modulate transcription levels. PD biomarkers exhibit dose dependence and a range of sensitivities with repeat dosing of I-66. COLO320DM tumor samples collected 48 hr post the 5thdose. For each, from left to right: vehicle, I-6630 mg / kg and I-66 75 mg / kg. (B): Axin2. (C): DKK4. (D): CXCL12. (E): NOTUM. (F): FGF20.

[0058] Figure 22. Provided technologies can reduce Notum polypeptide levels while increasing Notum mRNA levels. CRC PDX tumor (PIK3CA H1047R and mutant APC). Administration: IP. For each graphfrom left to right: protein and mRNA single-dose: vehicle (10 mg / mL arginine / 6% PEG400 phosphate), I-66 60 mg / kg 2 days post-dose, I-6660 mg / kg 7 days post-dose; mRNA 2 doses (Q4D): vehicle, I-47020 mg / kg 2 days post last dose, I-6620 mg / kg 2 days post last dose, I-6660 mg / kg 2 days post last dose, I-6660 mg / kg 7 days post last dose; mRNA 3 doses (Q4D): vehicle, I-47020 mg / kg 2 days post last dose, I-6620 mg / kg 2 days post last dose, I-6660 mg / kg 2 days post last dose, I-6660 mg / kg 7 days post last dose. ns: not significant; *, **, ***, and **** reflect different significance levels.

[0059] Figure 23. Provided technologies can reduce levels of Ki67. CRC PDX tumor (PIK3CA H1047R and mutant APC). Administration: IP. 2 doses (Q4D). From left to right: vehicle, I-47020 mg / kg 2 days post last dose, I-6620 mg / kg 2 days post last dose, I-6660 mg / kg 2 days post last dose, I-6660 mg / kg 7 days post last dose. ns: not significant; *, **, ***, and **** reflect different significance levels.

[0060] Figure 24. Provided technologies can reduce tumor growth in various models in vivo. For example, I-66 can reduce tumor volume in various models. (A)-(C): Y-axis is average tumor volume (mm3) and X-axis is days of treatment. Dotted vertical lines are doses. The top line is vehicle, and the bottom line is I-66. (A): Model 1. 60 mg / kg I-66. (B): Model 2. 60 mg / kg I-66. (C): Model 3. 50 mg / kg I-66. As confirmed, provided technologies can suppress tumor growth and / or lead to tumor stasis and / or regression in various tumors. (D): provided technologies can reduce tumor growth and / or lead to tumor stasis and / or regression in various tumors with APC mutations and optionally RAS and / or TP53 mutations. From left to right: 1stand 2nd: APC wild-type. 3rd-13th: APC mutant. The 5th: 73% TGI. The 6th: 65% TGI. Data shown were at d29+2 or at time of 3 doublings of vehicle treated tumor volume if later. I-66, Q4D, IP, 50-60 mg / kg, n=7-10.

[0061] Figure 25. Provided technologies can reduce tumor growth in vivo. For example, I-66 can reduce tumor growth at various doses. Model 2. #: end of in-life. *: one mouse euthanized due to large tumor size. 1: vehicle. 2: I-47020 mg / kg. 3: I-6610 mg / kg. 4: I-6620 mg / kg. 5: I-66: 35 mg / kg. 6: I-66 60 mg / kg. IP dosing, n=8 / group.

[0062] Figure 26. Provided technologies can reduce tumor growth in vivo. Among other things, Figure 26 confirms that provided technologies can suppress tumor growth and in some cases lead to tumor regression even with weekly administration. Model 2. Lines from top to bottom: vehicle; I-6620 mg / kg Q&D; I-6660 mg / kg Q7D (squares) and I-6660 mg / kg Q4D (triangles). The two 60 mg / kg largely overlap with each other. #: end of in-life.

[0063] Figure 27. Provided technologies can provide rapid regression. Among other things, Figure 27 confirms that provided technologies are active in vivo and can provide rapid tumor regression at various dose levels. Arrows indicate I-66 doses. Lines: top line at day 4 is vehicle, the second is I-47020 mg / kg; at day 8, from top going down are I-47020 mg / kg, I-6620 mg / kg and I-60 mg / kg. Model 2. 500mm3starting volume.

[0064] Figure 28. Provided technologies can modulate expression in vivo. (A) I-66 reduced Axin2 polypeptide levels in Model 2. From left to right: 2 days after second vehicle dose (Q4Dx2), 2 days after second 20 mg / kg dose (Q4Dx2) of I-470, 2 days after second 20 mg / kg dose (Q4Dx2) of I-66, 2 days aftersecond 60 mg / kg dose (Q4Dx2) of I-66, 7 days after second 60 mg / kg dose (Q4Dx2) of I-66. (B) I-66 reduced C-MYC polypeptide levels in Model 2. From left to right: two days after the second vehicle dose (Q4Dx2), two days after the second 20mg / kg dose (Q4Dx2) of I-470, two days after the second 20 mg / kg dose (Q4Dx2) of I-66, two days after the second 60 mg / kg dose (Q4Dx2) of I-66, and seven days after the second 60mg / kg dose (Q4Dx2) of I-66. Individual animals are shown as circles (n=8; data are presented as mean ± SD). Individual animals are shown as circles (n=6-8; data are presented as mean ± SD). Welch’s T- test was used for statistical evaluation for (G)-(I). p-values between 0.01 and 0.05 indicated as *, between 0.001 and 0.01 indicated as **, between 0.0001 and 0.001 as ***, and less than 0.0001 as ****. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Definitions

[0065] 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.

[0066] 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 selected period of time.

[0067] 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 becompared to a reference under comparable conditions (e.g., concentrations).

[0068] 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.

[0069] 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, 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.

[0070] Alkenyl: As used herein, the term “alkenyl” refers to an aliphatic group, as defined herein, having one or more double bonds.

[0071] 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 someembodiments, alkyl has 1-100 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).

[0072] 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 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.

[0073] 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 someembodiments, 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.

[0074] 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.

[0075] 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).

[0076] 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.

[0077] 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).

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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. Insome 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).

[0087] 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.

[0088] Halogen: The term “halogen” means F, Cl, Br, or I.

[0089] 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).

[0090] 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.

[0091] 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 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.

[0092] 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.

[0093] 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 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.

[0094] 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):

[0095] As will be understood by those skilled in the art, a variety of algorithms are available that 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.

[0096] 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 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 targetresidues (e.g., upon binding, docking or other interaction assays). In many embodiments, interaction residues are direct-binding residues.

[0097] “Improved,” “increased” 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.

[0098] 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.

[0099] 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.

[0100] 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 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; topicalapplication, 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.

[0101] 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.

[0102] 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.

[0103] 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, 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.

[0104] 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 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 oridentity 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.

[0105] 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.

[0106] 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– (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–butylcarbamate (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– 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.

[0107] 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.

[0108] 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.

[0109] 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, 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.

[0110] In some embodiments, a hydroxyl protecting group is acetyl, t-butyl, tbutoxymethyl, 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- (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 thehydroxyl 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.

[0111] 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.

[0112] 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.

[0113] 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).

[0114] 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 “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 thesame 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.

[0115] Suitable monovalent substituents are halogen; –(CH2)0–4R°; –(CH2)0–4OR°; −O(CH2)0-4R°, –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 –(C1–4straight or branched alkylene)C(O)O–N(R°)2; wherein each R° may be substituted as defined below and is independently hydrogen, C1–20(e.g., C1–15, C1–10, C1–6, C1–4, etc.) aliphatic, C1–20(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−(C6-14(e.g., C6-10, C6, C10, etc.) aryl), – O(CH2)0–1(C6-14(e.g., C6-10, C6, C10, etc.) aryl), −CH2-(5-14 (e.g., 5-10, 5-9, 5-6, etc.) membered heteroaryl ring), a 3–20 (e.g., 3-15, 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 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 3–20 (e.g., 3-15, 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 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.

[0116] 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●), –(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 eachR●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.

[0117] 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 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. 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, C1–6aliphatic which may 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.

[0118] 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.

[0119] 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, 5-10, 5-6, 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.

[0120] 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 sulfur.

[0121] 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., forexperimental, 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] Therapeutically effective amount: As used herein, the term “therapeutically effective amount” 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 subjectsuffering 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.

[0128] 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.

[0129] 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; 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 medicalarts.

[0130] Unsaturated: The term “unsaturated” as used herein, means that a moiety has one or more units of unsaturation.

[0131] Unless otherwise specified, salts, such as pharmaceutically acceptable acid or base addition salts, stereoisomeric forms, and tautomeric forms, of provided compound are included.

[0132] 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. Stapled Peptides

[0133] In some embodiments, a provided agent is or comprises a peptide. In some embodiments, a provided agent is a peptide. In some embodiments, a peptide is a stapled peptide. In some embodiments, a provided agent is 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, 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).

[0134] 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 someembodiments, there are three staples in a stapled peptide. In some embodiments, there are four staples in a stapled peptide.

[0135] 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 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, WO 2020 / 041270, WO 2022 / 020652, WO 2022 / 261257, etc., the staples of each of which are incorporated herein by reference.

[0136] 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. In some embodiments, a stapled peptide is as described in WO 2022 / 261257 which is incorporated herein by reference. In some embodiments, an peptide is as described in WO 2022 / 261257. In some embodiments, an agent is as described in WO 2022 / 261257.

[0137] 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.

[0138] 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 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.

[0139] 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 helix is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or more, amino acid residues.

[0140] 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 someembodiments, 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).

[0141] In some embodiments, a staple can be of various lengths, in some embodiments, as represent by 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 someembodiments, 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, 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.

[0142] 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.

[0143] 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.

[0144] 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 C9-13 aliphatic 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 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.

[0145] In some embodiments, a staple comprises a double bond. In some embodiments, a staplecomprises 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 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., C1-10alkynyl. 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.

[0146] In some embodiments, amino acids that are useful for stapling, or are stapled, are described in WO 2022 / 261257, e.g., those of formula A-II, A-II-b, A-III, A-IV, A-V, or A-VI, or salts thereof, which are incorporated herein by reference.

[0147] 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 E2 or Table E3) 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 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 is optionally substituted aliphatic, e.g., C1-10aliphatic. In someembodiments, 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., C1-10alkynyl. In some embodiments, −CHR’−CHR’− is −CH2−CH2−.

[0148] Table A-I. Exemplary amino acids (Fmoc-Protected).

[0149] Table A-II. Exemplary amino acids (Fmoc-Protected).

[0150] Table A-III. Exemplary amino acids (Fmoc-Protected).

[0151] In some embodiments, an amino acid is an alpha-amino acid. In some embodiments, an amino 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.

[0152] 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.

[0153] 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.

[0154] In some embodiments, two staples may be bonded to the same atom of the peptide backbone, forming a stitched peptide. In some embodiments, a staple is pro-lock wherein one end of the staple is bonded to the alpha-carbon of a proline residue. In some embodiments, a staple is a staple illustrated in Tables S-1, S-2, S-3, S-4, S-5 or S-6 of WO 2022 / 261257.

[0155] 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.

[0156] In some embodiments, a staple comprises −S−. In some embodiments, a staple is formed from cysteine stapling. Certain such staples are described in, e.g., WO 2022 / 261257.

[0157] Certain useful agents (peptides prior to stapling and stapled peptides post stapling) and compositions thereof are presented in Table E2 or Table E3 as examples, which includes various amino acid residues and N- and C-terminus capping groups for various positions as examples; also illustrated are variousstapling patterns, e.g., X1−X4−X11, X1−X3, X3−X7, X3−X10, X4−X11, X7−X10, X7−X14, X10−X14, etc. As demonstrated herein, provided technologies can deliver improved useful properties and / or activities.

[0158] In some embodiments, a provided agent, a peptide, or a stapled peptide is a compound as described herein. In some embodiments, a provided agent has a structure selected from Table E2 or Table E3, or a salt thereof. In some embodiments, a provided agent is a stereoisomer of a structure selected from Table E2 or Table E3, or a salt thereof. In some embodiments, a provided agent is a stereoisomer, with respect to a chiral center bonded to two staples (e.g., in B4, B5, etc.), of a structure selected from Table E2 or Table E3, or a salt thereof. In some embodiments, a provided agent is a stereoisomer, with respect to olefin double bond(s) in staple(s), of a structure selected from Table E2 or Table E3, or a salt thereof. In some embodiments, a provided agent is a stereoisomer, with respect to olefin double bond(s) in staple(s) and / or a chiral center bonded to two staples (e.g., in B4, B5, etc.), of a structure selected from Table E2 or Table E3, or a salt thereof. In some embodiments, a provided composition is a composition described in Table E2 or Table E3. In some embodiments, a compound has the structure ofor a salt thereof. In some embodiments, acompound has the structure ofor a salt thereof. In some embodiments, a compound has the structure ofor a salt thereof. In some embodiments, a compound has the structure ofor a salt thereof. In some embodiments, a compound has the structure of or a salt thereof. In some embodiments, acompound has the structure ofor a salt thereof. In some embodiments, a compound has the structure ofor a salt thereof. In someembodiments, a compound has the structure of) or a salt thereof. In some embodiments, a compound has the structure of or a salt thereof. In some embodiments, acompound has the structure ofor a salt thereof. In some embodiments, a compound has the structure of or a salt thereof. In some embodiments, acompound has the structure ofor a salt thereof. In some embodiments, a compound has the structure ofor a salt thereof. In some embodiments, a compound has the structure ofor a salt thereof. In some embodiments, a compound has the structure ofor a salt thereof. In some embodiments, a double bond of a (i, i+2) staple is E. In some embodiments, a double bondof a (i, i+2) staple is Z. In some embodiments, a double bond of a (i, i+3) staple is E. In some embodiments, a double bond of a (i, i+3) staple is Z. In some embodiments, a double bond of a (i, i+7) staple is E. In some embodiments, a double bond of a (i, i+7) staple is Z. In some embodiments, both double bonds are E. In some embodiments, both double bonds are Z. In some embodiments, a (i, i+3) staple is E, and the other is Z. In some embodiments, a (i, i+3) staple is Z, and the other is E. In some embodiments, a (i, i+4) staple is E, and the other is Z. In some embodiments, a (i, i+4) staple is Z, and the other is E. In some embodiments, a double bond of a (i, i+7) staple is Z, and a double bond of a second staple (e.g., (i, i+2), (i, i+3), (i, i+4), etc.) is E. In some embodiments, a double bond of a (i, i+7) staple is Z, and a double bond of a second staple (e.g., (i, i+2), (i, i+3), (i, i+4), etc.) is Z. In some embodiments, a double bond of a (i, i+7) staple is E, and a double bond of a second staple (e.g., (i, i+2), (i, i+3), (i, i+4), etc.) is E. In some embodiments, a double bond of a (i, i+7) staple is E, and a double bond of a second staple (e.g., (i, i+2), (i, i+3), (i, i+4), etc.) is Z. In some embodiments, two staples are bonded to a chiral center (e.g., a carbon atom in B5), and the chiral center is R. In some embodiments, two staples are bonded to a chiral center (e.g., a carbon atom in B5), and the chiral center is S.

[0159] In some embodiments, a compound has the structure selected from below or a salt thereof:In some embodiments, an agent is SP-1-1 or a salt thereof. In some embodiments, an agent is SP-1-2 or a salt thereof. In some embodiments, an agent is SP-1-3 or a salt thereof. In some embodiments, an agent is SP-1- 4 or a salt thereof. In some embodiments, an agent is SP-1-5 or a salt thereof. In some embodiments, an agent is SP-1-6 or a salt thereof. In some embodiments, an agent is SP-1-7 or a salt thereof. In some embodiments, an agent is SP-1-8 or a salt thereof. In some embodiments, an agent is SP-2-1 or a salt thereof.In some embodiments, an agent is SP-2-2 or a salt thereof. In some embodiments, an agent is SP-2-3 or a salt thereof. In some embodiments, an agent is SP-2-4 or a salt thereof. In some embodiments, an agent is SP-2- 5 or a salt thereof. In some embodiments, an agent is SP-2-6 or a salt thereof. In some embodiments, an agent is SP-2-7 or a salt thereof. In some embodiments, an agent is SP-2-8 or a salt thereof. In some embodiments, an agent is SP-3-1 or a salt thereof. In some embodiments, an agent is SP-3-2 or a salt thereof. In some embodiments, an agent is SP-4-1 or a salt thereof. In some embodiments, an agent is SP-4-2 or a salt thereof. In some embodiments, an agent is SP-4-3 or a salt thereof. In some embodiments, an agent is SP-4- 4 or a salt thereof. In some embodiments, an agent is SP-4-5 or a salt thereof. In some embodiments, an agent is SP-4-6 or a salt thereof. In some embodiments, an agent is SP-4-7 or a salt thereof. In some embodiments, an agent is SP-4-8 or a salt thereof. In some embodiments, an agent is SP-5-1 or a salt thereof. In some embodiments, an agent is SP-5-2 or a salt thereof. In some embodiments, an agent is SP-5-3 or a salt thereof. In some embodiments, an agent is SP-5-4 or a salt thereof. In some embodiments, an agent is SP-5- 5 or a salt thereof. In some embodiments, an agent is SP-5-6 or a salt thereof. In some embodiments, an agent is SP-5-7 or a salt thereof. In some embodiments, an agent is SP-5-8 or a salt thereof. In some embodiments, an agent is SP-6 or a salt thereof. In some embodiments, an agent is SP-7-1 or a salt thereof. In some embodiments, an agent is SP-7-2 or a salt thereof. In some embodiments, an agent is SP-7-3 or a salt thereof. In some embodiments, an agent is SP-7-4 or a salt thereof. In some embodiments, an agent is SP-7- 5 or a salt thereof. In some embodiments, an agent is SP-7-6 or a salt thereof. In some embodiments, an agent is SP-7-7 or a salt thereof. In some embodiments, an agent is SP-7-8 or a salt thereof. In some embodiments, an agent is SP-8-1 or a salt thereof. In some embodiments, an agent is SP-8-2 or a salt thereof. In some embodiments, an agent is SP-8-3 or a salt thereof. In some embodiments, an agent is SP-8-4 or a salt thereof. In some embodiments, an agent is SP-8-5 or a salt thereof. In some embodiments, an agent is SP-8- 6 or a salt thereof. In some embodiments, an agent is SP-8-7 or a salt thereof. In some embodiments, an agent is SP-8-8 or a salt thereof. In some embodiments, an agent is SP-9-1 or a salt thereof. In some embodiments, an agent is SP-9-2 or a salt thereof. In some embodiments, an agent is SP-9-3 or a salt thereof. In some embodiments, an agent is SP-9-4 or a salt thereof. In some embodiments, an agent is SP-9-5 or a salt thereof. In some embodiments, an agent is SP-9-6 or a salt thereof. In some embodiments, an agent is SP-9- 7 or a salt thereof. In some embodiments, an agent is SP-9-8 or a salt thereof. In some embodiments, an agent is SP-10-1 or a salt thereof. In some embodiments, an agent is SP-10-2 or a salt thereof. In some embodiments, an agent is SP-10-3 or a salt thereof. In some embodiments, an agent is SP-10-4 or a salt thereof. In some embodiments, an agent is SP-10-5 or a salt thereof. In some embodiments, an agent is SP- 10-6 or a salt thereof. In some embodiments, an agent is SP-10-7 or a salt thereof. In some embodiments, an agent is SP-10-8 or a salt thereof. In some embodiments, an agent is SP-11-1 or a salt thereof. In some embodiments, an agent is SP-11-2 or a salt thereof. In some embodiments, an agent is SP-11-3 or a salt thereof. In some embodiments, an agent is SP-11-4 or a salt thereof. In some embodiments, an agent is SP- 11-5 or a salt thereof. In some embodiments, an agent is SP-11-6 or a salt thereof. In some embodiments, anagent is SP-11-7 or a salt thereof. In some embodiments, an agent is SP-11-8 or a salt thereof. In some embodiments, an agent is SP-12-1 or a salt thereof. In some embodiments, an agent is SP-12-2 or a salt thereof. In some embodiments, an agent is SP-12-3 or a salt thereof. In some embodiments, an agent is SP-12-4 or a salt thereof. In some embodiments, an agent is SP-12-5 or a salt thereof. In some embodiments, an agent is SP-12-6 or a salt thereof. In some embodiments, an agent is SP-12-7 or a salt thereof. In some embodiments, an agent is SP-12-8 or a salt thereof. In some embodiments, an agent is SP-13-1 or a salt thereof. In some embodiments, an agent is SP-13-2 or a salt thereof. In some embodiments, an agent is SP-13-3 or a salt thereof. In some embodiments, an agent is SP-13-4 or a salt thereof. In some embodiments, an agent is SP-13-5 or a salt thereof. In some embodiments, an agent is SP-13-6 or a salt thereof. In some embodiments, an agent is SP-13-7 or a salt thereof. In some embodiments, an agent is SP-13-8 or a salt thereof. In some embodiments, an agent is SP-14-1 or a salt thereof. In some embodiments, an agent is SP-14-2 or a salt thereof. In some embodiments, an agent is SP-14-3 or a salt thereof. In some embodiments, an agent is SP-14-4 or a salt thereof. In some embodiments, an agent is SP-14-5 or a salt thereof. In some embodiments, an agent is SP-14-6 or a salt thereof. In some embodiments, an agent is SP-14-7 or a salt thereof. In some embodiments, an agent is SP-14-8 or a salt thereof. In some embodiments, an agent is SP-15-1 or a salt thereof. In some embodiments, an agent is SP-15-2 or a salt thereof. In some embodiments, an agent is SP-15-3 or a salt thereof. In some embodiments, an agent is SP-15-4 or a salt thereof. In some embodiments, an agent is SP-15-5 or a salt thereof. In some embodiments, an agent is SP-15-6 or a salt thereof. In some embodiments, an agent is SP-15-7 or a salt thereof. In some embodiments, an agent is SP- 15-8 or a salt thereof.

[0160] In some embodiments, an agent is selected from:or a salt thereof.

[0161] Agents, e.g., peptides including stapled peptides, can contain various numbers of amino acid residues. In some embodiments, a length of a peptide agent 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 acid residues. In some embodiments, a length is about 10 amino acid residues. In some embodiments, a length is about 11 amino acid residues. In some embodiments, a length is about 12 amino acid residues. In some embodiments, a length is about 13 amino acid residues. In some embodiments, a length is about 14 amino acid residues. In some embodiments, a length is about 15 amino acid residues. In some embodiments, a length is about 16 amino acid residues. In some embodiments, a length is about 17 amino acid residues. In some embodiments, a length is about 18 amino acid residues. In some embodiments, a length is about 19 amino acid residues. In some embodiments, a length is about 20 amino acid residues.

[0162] In some embodiments, as described herein, one or more staples independently comprise an olefin double bond (e.g., formed through olefin metathesis). In some embodiments, one or more staples independently comprise an amide group (e.g., formed through amidation). In some embodiments, at least one staple does not contain an olefin double bond. In some embodiments, there is at least one staple whose formation does not comprise reactions of olefins such as olefin metathesis and / or modification of olefin double bonds (e.g., hydrogenation, epoxidation, etc.).

[0163] In some embodiments, a residue of a staple (e.g., B5) is so positioned that if its position is P (e.g., X4), a first acidic amino acid residue is at position P-2 (e.g., X2), a second acidic amino acid residue is positioned at P+1 (e.g., X5), a third acidic amino acid residue is positioned at P+2 (e.g., X6), a hydrophobic amino acid residue is positioned at P+4 (e.g., X8), a first aromatic amino acid residue is positioned at P+5 (e.g., X9), a second aromatic amino acid residue is positioned at P+8 (e.g., X12), and / or a third aromatic amino acid residue is positioned at P+9 (e.g., X13). In some embodiments, a staple is a (i, i+7) staple, and the other residue of the staple is positioned at P+7 (e.g., X11). In some embodiments, a first acidic amino acid residue is at position P-2 (e.g., X2). In some embodiments, a second acidic amino acid residue is positioned at P+1 (e.g., X5). In some embodiments, a third acidic amino acid residue is positioned at P+2 (e.g., X6). In some embodiments, a hydrophobic amino acid residue is positioned at P+4 (e.g., X8). In some embodiments, a first aromatic amino acid residue is positioned at P+5 (e.g., X9). In some embodiments, a second aromatic amino acid residue is positioned at P+8 (e.g., X12). In some embodiments, a third aromatic amino acid residue is positioned at P+9 (e.g., X13). In some embodiments, a first acidic amino acid residue is at position P-2 (e.g., X2), a second acidic amino acid residue is positioned at P+1 (e.g., X5), a first aromatic amino acid residue is positioned at P+5 (e.g., X9), a second aromatic amino acid residue is positioned at P+8 (e.g., X12), and a third aromatic amino acid residue is positioned at P+9 (e.g., X13). In some embodiments, a first acidic amino acid residue is at position P-2 (e.g., X2), a second acidic amino acid residue is positioned at P+1 (e.g., X5), a third acidic amino acid residue is positioned at P+2 (e.g., X6), a hydrophobic amino acid residue is positioned at P+4 (e.g., X8), a first aromatic amino acid residue is positioned at P+5 (e.g., X9), a second aromatic amino acid residue is positioned at P+8 (e.g., X12), and a third aromatic amino acid residue is positioned at P+9 (e.g.,X13). In some embodiments, a stapled peptide agent comprises acidic amino acid residues at positions P-2 and P+1, and aromatic amino acid residues at positions P+5, P+8 and P+9. In some embodiments, a stapled peptide agent comprises acidic amino acid residues at positions P-2, P+1 and P+2, and aromatic amino acid residues at positions P+5, P+8 and P+9. In some embodiments, a stapled peptide agent comprises acidic amino acid residues at positions P-2 and P+1, a hydrophobic amino acid residue at position P+4, and aromatic amino acid residues at positions P+5, P+8 and P+9. In some embodiments, a stapled peptide agent comprises acidic amino acid residues at positions P-2, P+1 and P+2, a hydrophobic amino acid residue at position P+4, and aromatic amino acid residues at positions P+5, P+8 and P+9. In some embodiments, P is 3. In some embodiments, P is 4. In some embodiments, P is 5. In some embodiments, P is 6. In some embodiments, P is 7. In some embodiments, an amino acid residue at position P comprises two groups for stapling, e.g., B4, B5, B6, etc. In some embodiments, it is B4. In some embodiments, it is B5. In some embodiments, it is B6. In some embodiments, an agent comprises a staple and a first additional staple, e.g., a (i, i+3) or (i, i+4) staple. In some embodiments, a staple and a first additional staple are bonded to the same residue (e.g., B5, B6, etc.). In some embodiments, the other residue of a first additional residue is at position P-2 (e.g., when a moiety for stapling like a terminal olefin is in a P-terminal group which is considered a portion of X1), P-3 or P-4. In some embodiments, an agent comprises a second additional staple, e.g., a (i, i+4) staple (e.g., stapling residues at positions P+6 (e.g., X10) and P+10 (e.g., X14), a (i, i+3) staple (e.g., stapling residues at positions P+3 (e.g., X7) and P+6 (e.g., X10), a (i, i+7) staple (e.g., stapling residues at positions P+3 (e.g., X7) and P+10 (e.g., X14), etc.). In some embodiments, an agent comprises a second additional staple which is a (i, i+4) staple stapling residues at positions P+6 (e.g., X10) and P+10 (e.g., X14). In some embodiments, an agent comprises a third additional staple, e.g., a (i, i+4) staple stapling residues at positions P-1 (e.g., X3) and P+3 (e.g., X7). In some embodiments, there are three staples in a stapled peptide agent. In some embodiments, there are four staples in a stapled peptide agent. As demonstrated herein, stapled agents comprising so positioned staples and residues can provide various desired properties and activities. In some embodiments, positioning of one or more staples may be shifted relevant to various acidic, hydrophobic and / or aromatic amino acid residues described herein, e.g., in some embodiments, stapled peptide agents comprise stapled residues at position P and P+7 (and optionally P-3 or P-4), acidic amino acid residues are at positions P-1, and P+2, and aromatic amino acid residues at positions P+6, P+9 and P+10, and optionally an acid amino acid residue at P+3 and / or a hydrophobic amino acid residue at position P+5. It was observed that various stapled peptide agents with shifted staples can bind to beta-catenin when assessed by fluorescence polarization.

[0164] Certain useful staples are described in the “Agents” section, below.

[0165] Certain stapled peptides are described in WO 2022 / 020652 and WO 2022 / 261257, the stapled peptides of each of which are independently incorporated herein by reference. Beta-catenin

[0166] Among other things, the present disclosure provides technologies for modulating one or more beta-catenin functions. In some embodiments, the present disclosure provides useful technologies for inhibiting one or more beta-catenin functions that are associated with cancer or hyperplasia. In some embodiments, provided technologies are useful for preventing and treating conditions, disorders or diseases whose prevention and / or treatment will benefits from inhibition of beta-catenin. In some embodiments, a condition, disorder or disease is cancer.

[0167] Beta-catenin is reported to have various functions. For example, it can regulate and coordinate transcription of various genes. It is reported that high beta-catenin activity and / or expression levels may contribute to the development various conditions, disorders or diseases including cancer. Mutations and overexpression of beta-catenin are reported to be associated with conditions, disorders or diseases including many cancers including colorectal cancer, lung cancer, and breast cancer. Dysregulation of the Wnt / β- catenin signaling pathway has reportedly been linked to a number of conditions, disorders or diseases, including neurodegenerative diseases, psychiatric diseases, cancers, asthma, and even wound healing. An abundance of published research, both clinical and preclinical, has indicated that hyperactivated Wnt / beta- catenin activity drives tumorigenesis and is required for tumor maintenance in various cancers. Many Wnt inhibitors largely modulate this pathway at the extracellular ligand / receptor level, e.g., by preventing Wnt ligand secretion or by blocking Wnt ligand interaction with its receptors at the plasma membrane. It has been reported that many activating Wnt pathway mutations are found in APC and / or CTNNB1, which are downstream of membrane-proximal events. Among other things, the present disclosure encompasses the recognition that many agents at the extracellular ligand / receptor level are insufficient to treat many relevant patients, e.g., those with downstream mutations / abnormalities. In some embodiments, Wnt pathway- activating mutations converge on beta-catenin / TCF node. In some embodiments, the present disclosure targets beta-catenin / TCF interaction, e.g., as a therapeutic approach. Agents that can modulate beta-catenin functions are useful for various purposes including preventing and / or treating various conditions, disorders or diseases associated with beta-catenin.

[0168] In some embodiments, beta-catenin is in a mutant form which comprises one or more mutations. In some embodiments, a mutant form is associated with a condition, disorder or disease. Binding Sites

[0169] Beta-catenin may interact with various agents at various binding sites each independently comprising a set of amino acid residues that interact with binding agents. For example, certain binding sites are utilized for beta-catenin interactions with Axin, APC, C-cadherin, E-cadherin, TCF3, and Bcl9. For interactions with TCF3, it has been reported that two or more binding sites may be utilized simultaneously to interact with different portions of TCF3. See, e.g., Graham et al. Cell, Vol.103, 885–896, 2000.

[0170] In some embodiments, provided agents bind to beta-catenin at a unique binding site. In some embodiments, provided agents interact with beta-catenin at a set of amino acid residues that are differentfrom previously reported binding sites, e.g., those for Axin, APC, C-cadherin, E-cadherin, TCF3 or Bcl9.

[0171] For example, in some embodiments, provided agents interact with one or more or all (e.g., about 1-23, 1-20, 1-15, 1-10, 1-5, 5-23, 5-20, 5-15, 5-10, 6-23, 6-20, 6-15, 6-10, 7-23, 7-20, 7-15, 7-10, 8-23, 8-20, 8-15, 8-10, 9-23, 9-20, 9-15, 9-10, 10-23, 10-20, 10-15, 11-23, 11-20, 11-15, 12-23, 12-20, 12-15, 13-23, 13- 20, 13-15, 13-23, 14-20, 15-23, 15-20, 16-23, 16-20, 17-23, 17-20, 18-23, or 18-20, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, etc.) of a set of amino acid residues that are or correspond to amino acid residues in SEQ ID NO: 1, e.g., in some embodiments, the following amino acid 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, a set of amino acid residues are or correspond to amino acid residues 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, a set of amino acid residues are or correspond to amino acid residues 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, a set of amino acid residues are or correspond to amino acid residues G307, K312, K345, W383, N387, D413, and N415 of SEQ ID NO: 1. In some embodiments, a set of amino acid residues are or correspond to amino acid residues G307, K312, K345, Q379, L382, W383, N387, N415 and V416 of SEQ ID NO: 1. In some embodiments, a set of amino acid residues are or correspond to amino acid residues Y306, G307, K312, K345, Q379, L382, W383, N387, N415 and V416 of SEQ ID NO: 1. In some embodiments, a set of amino acid residues are or correspond to amino acid residues G307, K312, K345, Q379, L382, W383, R386, N387, N415 and V416 of SEQ ID NO: 1. In some embodiments, a set of amino acid residues are or correspond to amino acid residues Y306, G307, K312, K345, Q379, L382, W383, R386, N387, N415 and V416 of SEQ ID NO: 1. In some embodiments, a set of amino acid residues are or correspond to amino acid residues Y306, G307, K312, K345, V349, Q379, L382, W383, N387, N415 and V416 of SEQ ID NO: 1. In some embodiments, a set of amino acid residues are or correspond to amino acid residues Y306, G307, K312, K345, V349, Q379, L382, W383, R386, N387, N415 and V416 of SEQ ID NO: 1. In some embodiments, a set of amino acid residues are or correspond to amino acid residues G307, K312, K345, W383, and N387 of SEQ ID NO: 1. In some embodiments, a set of amino acid residues are or correspond to amino acid residues Y306, G307, K312, R386 and N387 of SEQ ID NO: 1. In some embodiments, provided agents interact with Y306 or an amino acid residue corresponding thereto. In some embodiments, provided agents interact with G307 or an amino acid residue corresponding thereto. In some embodiments, provided agents interact with K312 or an amino acid residue corresponding thereto. In some embodiments, provided agents interact with K345 or an amino acid residue corresponding thereto. In some embodiments, provided agents interact with V349 or an amino acid residue corresponding thereto. In some embodiments, provided agents interact with Q379 or an amino acid residue corresponding thereto. In some embodiments, provided agents interact with L382 or an amino acid residue corresponding thereto. In some embodiments, provided agents interact with W383 or an amino acid residue correspondingthereto. In some embodiments, provided agents interact with R386 or an amino acid residue corresponding thereto. In some embodiments, provided agents interact with N387 or an amino acid residue corresponding thereto. In some embodiments, provided agents interact with N415 or an amino acid residue corresponding thereto. In some embodiments, provided agents interact with V416 or an amino acid residue corresponding thereto.

[0172] In some embodiments, a present agent interacts with a polypeptide whose sequence corresponds to aa 146-aa665 of human beta-catenin. In some embodiments, a present agent interacts with a polypeptide whose sequence comprises or is SEQ ID NO: 2: SVLFYAITTLHNLLLHQEGAKMAVRLAGGLQKMVALLNKTNVKFLAITTDCLQILAYGNQESKLIIL ASGGPQALVNIMRTYTYEKLLWTTSRVLKVLSVCSSNKPAIVEAGGMQALGLHLTDPSQRLVQNCL WTLRNLSDAATKQEGMEGLLGTLVQLLGSDDINVVTCAAGILSNLTCNNYKNKMMVCQVGGIEAL VRT (SEQ ID NO: 2).

[0173] In some embodiments, all amino acid residues that interact with a provided agent is with SEQ ID NO: 2. In some embodiments, amino acid residues that interact with a provided agent (e.g., one or more amino acid residues in an agent) interacts with an agent through hydrogen bonding, hydrophobic interactions or salt bridge. As appreciated by those skilled in the art, when two amino acid residues interacting with each other, they are typically within a certain range of distances when, e.g., assessed using crystallography, NMR, etc.

[0174] In some embodiments, certain amino acid residues reported to interact with one or more polypeptides are not significantly involved in interactions between provided and beta-catenin. In some embodiments, provided agents do not interact with an Axin binding site. In some embodiments, provided agents do not interact with a Bcl9 binding site. In some embodiments, provided agents do not interact with one or more or all of amino acid residues that are or correspond to N426, C429, K435, R469, H470, S473, R474, K508 and N516 of SEQ ID NO: 1. In some embodiments, provided agents do not interact with N426 or an amino acid residue corresponding thereto. In some embodiments, provided agents do not interact with C429 or an amino acid residue corresponding thereto. In some embodiments, provided agents do not interact with K435 or an amino acid residue corresponding thereto. In some embodiments, provided agents do not interact with R469 or an amino acid residue corresponding thereto. In some embodiments, provided agents do not interact with H470 or an amino acid residue corresponding thereto. In some embodiments, provided agents do not interact with S473 or an amino acid residue corresponding thereto. In some embodiments, provided agents do not interact with R474 or an amino acid residue corresponding thereto. In some embodiments, provided agents do not interact with K508 or an amino acid residue corresponding thereto. In some embodiments, provided agents do not interact with N516 or an amino acid residue corresponding thereto.

[0175] In some embodiments, mutation of one or more amino acid residues outside of SEQ ID NO: 2 in beta-catenin does not significantly (e.g., not exceeding 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90% ormore) reduce interactions of beta-catenin with a provided agent. In some embodiments, mutation of one or more or all of amino acid residues that are or correspond to N426, C429, K435, R469, H470, S473, R474, K508 and N516 of SEQ ID NO: 1 does not significantly reduce interactions of beta-catenin with a provided agent. In some embodiments, mutation of N426 or an amino acid residue corresponding thereto does not significantly reduce interaction of beta-catenin with an agent. In some embodiments, mutation of Q379 or an amino acid residue corresponding thereto (e.g., to Ala, Glu, Phe, Trp, etc.) does not significantly reduce interaction of beta-catenin with an agent.

[0176] In some embodiments, an agent binds to a TCF site of beta-catenin. In some embodiments, an agent interacts with one or more but not all amino acid residues that interact with TCF. In some embodiments, an agent interacts with one or more but not all amino acid residues that interact with an extended region of XTcf3-CBD. In some embodiments, an agent does not interact with beta-catenin amino acid residues that interact with a beta-hairpin module of XTcf3-CBD. In some embodiments, an agent does not interact with beta-catenin amino acid residues that interact with a helix module of XTcf3-CBD. For certain amino acid residues that interact various modules of XTcF3-CBD, see, e.g., Graham et al. Cell, Vol. 103, 885–896, 2000.

[0177] In some embodiments, an agent competes with TCF for beta-catenin binding. In some embodiments, an agent competes with an extended region of TCF (e.g., Ala14-Glu24, or Asp16-Glu24, as described in Graham et al. Cell, Vol.103, 885–896, 2000) for beta-catenin binding. In some embodiments, compared to an extended region of TCF, an agent does not compete, or competes at a less degree, with Axin for beta-catenin binding. In some embodiments, compared to an extended region of TCF, an agent does not compete, or competes at a less degree, with Bcl9 for beta-catenin binding. In some embodiments, compared to an extended region of TCF, an agent does not compete, or competes at a less degree, with a beta-hairpin module of XTcf3-CBD for beta-catenin binding. In some embodiments, compared to an extended region of TCF, an agent does not compete, or competes at a less degree, with a helix module of XTcf3-CBD for beta- catenin binding. In some embodiments, an agent competes with E-cadherin for beta-catenin binding.

[0178] In some embodiments, the present disclosure provides complexes of peptides (e.g., polypeptides whose sequences are or comprises SEQ ID NO: 1 or 2) and provided agents. In some embodiments, in such complexes polypeptides and provided agents interact with one or more or all amino acid residues as described herein, and optionally do not interact with one or more or all amino acid residues as described herein.

[0179] In some embodiments, the present disclosure provides complexes comprising a provided agent and a beta-catenin polypeptide or a portion thereof. In some embodiments, a portion thereof comprises one or more or all of the interacting residues as described herein. In some embodiments, an agent and a beta- catenin polypeptide or a portion thereof interact with other at one or more or all of the interacting residues. Certain Agents

[0180] In some embodiments, the present disclosure provides an agent having 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 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; 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, ortwo 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.

[0181] In some embodiments, the present disclosure provides an agent having 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, 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 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.

[0182] In some embodiments, a compound of formula I is a stapled peptide as described herein.

[0183] Various agents, including embodiments for various variables, e.g., R’, R, RN, LP1, LAA1, LP2, LAA2, LP3, LAA3, LP4, LAA4, LP5, LAA5, LP6, LAA6, LP7, RC, LAS, etc., are described in WO 2022 / 261257 and incorporated herein by reference.

[0184] For example, 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−. In some embodiments, such a carbon atom is an alpha carbon of an amino acid residue. In some embodiments, LAA1is X2as described herein. 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. In some embodiments, LAA2is X5as described herein. 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, LAA3is X8as described herein. In some embodiments, LP4is or comprises −[X]pX7X8[X]p’−, wherein each X, X7and X8is independently an amino acid residue, and each of p and p’ is independently 0- 10. In some embodiments, LP4is or comprises −X7X8−, wherein each X7and X8is independently as described herein, and X8is bonded to LAA4. In some embodiments, LAA4is X9as described herein. In some embodiments, LP5is or comprises −[X]pX11[X]p’−, wherein each variable is independently as described herein. In some embodiments, LP5is or comprises −X10X11−, wherein each X10and X11is independently as described herein, and X11is bonded to LAA5. In some embodiments, LAA5is or comprises amino acid residue. In some embodiments, LAA5is or comprises an amino acid residue that comprises a side chain comprising an aromatic group. In some embodiments, LAA5is X12as described herein. In some embodiments, LP6is or comprises an amino acid residue. In some embodiments, LP6is or comprises a peptide. In some embodiments, LAA6is X13as described herein. In some embodiments, LP7is or comprises −X14−[X]p’−, wherein p’ is 0-10. In some embodiments, X14is bonded to LAA6.

[0185] In some embodiments, an agent of formula I is a stapled peptide as described herein. In some embodiments, an agent of formula I is an agent selected from Table E2 or a pharmaceutically acceptable salt thereof. In some embodiments, an agent of formula I is an agent selected from Table E3 or a pharmaceutically acceptable salt thereof.

[0186] Among other things, the present disclosure provides agents, e.g. peptides, that can bind to beta- catenin. In some embodiments, an agent is or comprises X1X2X3X4X5X6X7X8X9X10X11X12X13X14wherein each of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13and X14is independently an amino acid residue. In some embodiments, an agent is or comprises [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17, wherein each of p0, p15, p16 and p17 is independently 0 or 1, and each of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, and X17is independently an amino acid residue.

[0187] Various amino acid residues, e.g., those of formula A-I, A-II, A-III, A-IV, A-V, A-VI, PA, etc., can be utilized in accordance with the present disclosure. Certain useful amino acid residues are described in the present disclosure.

[0188] In some embodiments, each of X2and X5is independently an acidic residue as described herein. In some embodiments, each of X2, X5and X6is independently an acidic residue as described herein. In some embodiments, each of X9, X12and X13are independently an amino acid residue comprising a side chain that comprises an aromatic group.

[0189] In some embodiments, X2is an acidic residue. In some embodiments, X2comprises a side chain that comprises −COOH or a derivative thereof. In some embodiments, X2comprises a side chain that comprises −COOH. In some embodiments, X2is Asp. Various other amino acid residues for X2are described else in the present disclosure.

[0190] In some embodiments, X5is an acidic residue. In some embodiments, X5comprises a side chain that comprises −COOH or a derivative thereof. In some embodiments, X5comprises a side chain that comprises −COOH. In some embodiments, X5is Asp. Various other amino acid residues for X5are described else in the present disclosure.

[0191] In some embodiments, X6is an acidic residue. In some embodiments, X6comprises a side chain that comprises −COOH or a derivative thereof. In some embodiments, X6comprises a side chain that comprises −COOH. In some embodiments, X6is Asp. Various other amino acid residues for X6are described else in the present disclosure.

[0192] In some embodiments, X9comprises a side chain that comprises an aromatic group. In some embodiments, X9comprises a side chain that comprises −R, wherein R is an optionally substituted group selected from phenyl, 10-membered bicyclic aryl, 5-membered heteroaryl having 1-3 hetereoatoms, and 9-10 membered bicyclic heteroaryl having 1-5 heteroatoms. In some embodiments, each heteroatom is independently sleeved from nitrogen, oxygen and sulfur. In some embodiments, X9is Phe. Various other amino acid residues for X9are described else in the present disclosure.

[0193] In some embodiments, X12comprises a side chain that comprises an aromatic group. In some embodiments, X12comprises a side chain that comprises −R, wherein R is an optionally substituted group selected from phenyl, 10-membered bicyclic aryl, 5-membered heteroaryl having 1-3 hetereoatoms, and 9-10 membered bicyclic heteroaryl having 1-5 heteroatoms. In some embodiments, each heteroatom is independently sleeved from nitrogen, oxygen and sulfur. In some embodiments, X12is 3Thi. In some embodiments, X12is 2F3MeF. In some embodiments, X12is Phe. Various other amino acid residues for X12are described else in the present disclosure.

[0194] In some embodiments, X13comprises a side chain that comprises an aromatic group. In some embodiments, X13comprises a side chain that comprises −R, wherein R is an optionally substituted group selected from phenyl, 10-membered bicyclic aryl, 5-membered heteroaryl having 1-3 hetereoatoms, and 9-10 membered bicyclic heteroaryl having 1-5 heteroatoms. In some embodiments, each heteroatom is independently sleeved from nitrogen, oxygen and sulfur. In some embodiments, X13is BtzA. In some embodiments, X13is 34ClF. In some embodiments, X13is 2NapA. Various other amino acid residues for X13are described else in the present disclosure.

[0195] As described herein, in some embodiments, a peptide is a stapled peptide. In some embodiments, an agent is or comprises a peptide, wherein a peptide is a stapled peptide. In some embodiments, a peptide is a stitched peptide. In some embodiments, a peptide comprises three or more staples as described herein. In some embodiments, a peptide comprises three or more staples within a region having a length of, e.g., 11-15, such as 11, 14, etc., amino acid residues as described herein. In some embodiments, such a peptide provides improved rigidity, activity, delivery, solubility, and / or other desired properties comprising a reference peptide that is not stapled or that comprises fewer staples.

[0196] In some embodiments, the present disclosure provides an agent, e.g., a peptide, comprising X1X2X3X4X5X6X7X8X9X10X11X12X13X14, wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14are each independently an amino acid residue and comprises two or more pairs of amino acid residues, wherein each pair of amino acid residues are independently two amino acid residues suitable for stapling or stapled. In some embodiments, the present disclosure provides an agent, e.g., a peptide, comprising X1X2X3X4X5X6X7X8X9X10X11X12X13X14, wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14are each independently an amino acid residue and comprises two or more pairs of amino acid residues, wherein each pair of amino acid residues are independently three amino acid residues suitable for stapling or stapled.

[0197] In some embodiments, the present disclosure provides an agent, e.g., a peptide, comprising [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17, wherein each of p0, p15, p16 and p17 is independently 0 or 1, and X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, and X17are each independently an amino acid residue and comprises two or more pairs of amino acid residues, wherein each pair of amino acid residues are independently two amino acid residues suitable for stapling or stapled. In some embodiments, the present disclosure provides an agent, e.g., a peptide, comprising [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17, wherein each of p0, p15, p16 and p17 is independently 0 or 1, and X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, and X17are each independently an amino acid residue and comprises three or more pairs of amino acid residues, wherein each pair of amino acid residues are independently two amino acid residues suitable for stapling or stapled. In some embodiments, each amino acid residue in such pairs of amino acid residues are independently selected from X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14.

[0198] In some embodiments, there are three such pairs of amino acid residues. In some embodiments, there are four such pairs of amino acid residues. In some embodiments, there are four or more such pairs of amino acid residues. In some embodiments, each pair is independently not stapled. In some embodiments, one or more pairs are independently stapled. In some embodiments, two or more pairs are independently stapled. In some embodiments, three or more pairs are independently stapled. In some embodiments, four or more pairs are independently stapled. In some embodiments, two pairs are independently stapled. In some embodiments, three pairs are independently stapled. In some embodiments, four pairs are independently stapled.

[0199] In some embodiments, a pair is X1and X4. In some embodiments, a pair is X4and X11. In some embodiments, a pair is X1and X3. In some embodiments, a pair is X4and X11. In some embodiments, a pair is X10and X14. In some embodiments, a pair is X7and X10. In some embodiments, a pair is X7and X14. In some embodiments, a pair is X3and X7.

[0200] In some embodiments, a pair is X1and X14and a pair is X4and X11. In some embodiments, a pair is X1and X14, a pair is X4and X11and a pair is X10and X14. In some embodiments, a pair is X1and X14, a pair is X4and X11and a pair is X7and X10. In some embodiments, a pair is X1and X14, a pair is X4and X11and a pair is X7and X14. In some embodiments, a pair is X1and X14, a pair is X4and X11, a pair is X3and X7, and a pair is X7and X14. In some embodiments, each pair is independently a pair of amino acid residues suitable for stapling. In some embodiments, each pair is independently stapled.

[0201] In some embodiments, a pair is X1and X3, a pair is X4and X11, and a pair is X10and X14. In some embodiments, each pair is independently a pair of amino acid residues suitable for stapling. In some embodiments, each pair is independently stapled.

[0202] In some embodiments, the present disclosure provides an agent, which is or comprises a peptide comprising: [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17, wherein: each of p0, p15, p16 and p17 is independently 0 or 1; each of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, and X17is independently an amino acid residue, wherein the agent binds to beta-catenin.

[0203] In some embodiments, X2comprises a side chain comprising an acidic or a polar group. In some embodiments, X2comprises a side chain comprising an acidic group. In some embodiments, X2comprises a side chain comprising a polar group. In some embodiments, X5comprises a side chain comprising an acidic or a polar group. In some embodiments, X5comprises a side chain comprising an acidic group. In some embodiments, X5comprises a side chain comprising a polar group. In some embodiments, X13comprises a side chain comprising an optionally substituted aromatic group. In some embodiments, 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.

[0204] In some embodiments, the present disclosure provides an agent, which is or comprises a peptide comprising: [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17, wherein: each of p0, p15, p16 and p17 is independently 0 or 1; each of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, and X17is 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. In some embodiments, three or more of X1, X3, X4, X7, X10, X11and X14are each independently an amino acid residue suitable for stapling, or are each independently stapled. In some embodiments, four or more of X1, X3, X4, X7, X10, X11and X14are each independently an amino acid residue suitable for stapling, or are each independently stapled. In some embodiments, five of X1, X3, X4, X7, X10, X11and X14are each independently an amino acid residue suitable for stapling, or are each independently stapled. In some embodiments, X1and X4are each independently an amino acid residue suitable for stapling. In some embodiments, X1and X3are each independently an amino acid residue suitable for stapling. In some embodiments, X4and X11are each independently an amino acid suitable for stapling. In some embodiments, X1, X4, and X11are each independently an amino acid residue suitable for stapling. In some embodiments, X10and X14are each independently an amino acid residue suitable for stapling. In some embodiments, X7and X10are each independently an amino acid residue suitable for stapling. In some embodiments, X7and X14are each independently an amino acid residue suitable for stapling. In some embodiments, X3and X7are each independently an amino acid residue suitable for stapling. In some embodiments, X1and X4are connected by a staple. In some embodiments, X1and X3are connected by a staple. In some embodiments, X4and X11are connected by a staple. In some embodiments, X1and X4connected by a staple, and X4and X11are connected by a staple. In some embodiments, X10and X14are connected by a staple. In some embodiments, X7and X10are connected by a staple. In some embodiments, X7and X14are connected by a staple. In some embodiments, X3and X7are connected by a staple.

[0205] In some embodiments, the present disclosure provides an agent, which is or comprises a peptide comprising: [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17, wherein: each of p0, p15, p16 and p17 is independently 0 or 1; each of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, and X17is 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 wherein: X1and X4are connected by a staple and / or X4and X11are connected by a staple, and X10and X14are connected by a staple.

[0206] In some embodiments, the present disclosure provides an agent, which is or comprises a peptide comprising: [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17,wherein: each of p0, p15, p16 and p17 is independently 0 or 1; each of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, and X17is 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 wherein: X1and X4are connected by a staple and / or X4and X11are connected by a staple, and X7and X10are connected by a staple.

[0207] In some embodiments, the present disclosure provides an agent, which is or comprises a peptide comprising: [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17, wherein: each of p0, p15, p16 and p17 is independently 0 or 1; each of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, and X17is 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 wherein: X1and X4are connected by a staple and / or X4and X11are connected by a staple, and X7and X14are connected by a staple.

[0208] In some embodiments, the present disclosure provides an agent, which is or comprises a peptide comprising: [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17, wherein: each of p0, p15, p16 and p17 is independently 0 or 1; each of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, and X17is 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 wherein: X1and X4are connected by a staple and / or X4and X11are connected by a staple; and X10and X14are connected by a staple and / or X3and X7are connected by a staple.

[0209] In some embodiments, the present disclosure provides an agent, which is or comprises a peptide comprising: [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17,wherein: each of p0, p15, p16 and p17 is independently 0 or 1; each of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, and X17is 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 wherein: X1and X3are connected by a staple, X4and X11are connected by a staple; and X10and X14are connected by a staple.

[0210] In some embodiments, X2comprises a side chain comprising an acidic (e.g., −COOH) or a polar group. In some embodiments, X2comprises a side chain comprising an acid group. In some embodiments, X5comprises a side chain comprising an acidic or a polar group. In some embodiments, X5comprises a side chain comprising an acid group. In some embodiments, X6comprises a side chain comprising an acidic or a polar group. In some embodiments, X6comprises a side chain comprising an acid group. In some embodiments, X9comprises a side chain comprising an optionally substituted aromatic group. In some embodiments, X12comprises a side chain comprising an optionally substituted aromatic group. In some embodiments, X13comprises a side chain comprising an optionally substituted aromatic group. In some embodiments, X2and X5each independently comprise a side chain comprising an acidic or a polar group. In some embodiments, X2and X6each independently comprise a side chain comprising an acidic or a polar group. In some embodiments, X5and X6each independently comprise a side chain comprising an acidic or a polar group. In some embodiments, X2and X5each independently comprise a side chain comprising an acidic group. In some embodiments, X2and X6each independently comprise a side chain comprising an acidic group. In some embodiments, X5and X6each independently comprise a side chain comprising an acidic group. In some embodiments, X2, X5and X6each independently comprise a side chain comprising an acidic or a polar group. In some embodiments, X2, X5and X6each independently comprise a side chain comprising an acidic group. In some embodiments, each of X9and X12independently comprises a side chain comprising an optionally substituted aromatic group. In some embodiments, each of X9and X13independently comprises a side chain comprising an optionally substituted aromatic group. In some embodiments, each of X9, X12and X13independently comprises a side chain comprising an optionally substituted aromatic group. In some embodiments, each of X2and X5independently comprises a side chain comprising an acidic group (e.g., −COOH), and each of X9, X12and X13independently comprises a side chain comprising an optionally substituted aromatic group. In some embodiments, each of X2, X5and X6independently comprises a side chain comprising an acidic group (e.g., −COOH), and each of X9, X12and X13independently comprises a side chain comprising an optionally substituted aromatic group.

[0211] As described herein, various types of amino acid residues (e.g., those of amino acids having the structure of formula A-I, A-II, A-III, A-IV, A-V, A-VI, etc. as described herein or in WO 2022 / 261257 andincorporated herein by reference) can be utilized in accordance with the present disclosure. Certain examples are described herein for X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, etc.

[0212] Various embodiments are described for p0, X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, etc. in WO 2022 / 261257 and are incorporated by reference.

[0213] For example, in some embodiments, X1is an amino acid reside suitable for stapling. In some embodiments, X1is stapled. In some embodiments, X1is PL3. In some embodiments, −Cy− is optionally substituted phenylene. PL3. In some embodiments, X2is a residue of amino acid (e.g., of formula A-I, A-II, A-III, A-IV, A-V, A-VI, etc. or a salt thereof) that comprises an acidic or polar group. In some embodiments, X2is a residue of amino acid whose side chain comprises an acidic group (in some embodiments, may be referred to as an “acidic amino acid residue”). In some embodiments, X2is Asp. In some embodiments, X2is Glu. In some embodiments, X3is a hydrophobic amino acid residue. In some embodiments, X3is a residue of an amino acid whose side chain is C1-10aliphatic optionally substituted with one or more non-polar and non-charged groups. In some embodiments, it is a residue of an amino acid whose side chain is C1-10aliphatic optionally substituted with one or more hydrophobic substituents. In some embodiments, it is a residue of an amino acid whose side chain is C1-10aliphatic. In some embodiments, it is a residue of an amino acid whose side chain is C1-10alkyl. In some embodiments, X3is a residue of Ala, Val, Ile, Leu, Met, Phe, Tyr, Trp, Npg, Leu, Cha, Val, nLeu, Ile, CypA, CyLeu, Chg, DiethA, Ala, Aib, OctG, or Cba. In some embodiments, X3is a residue of Npg, Leu, or Cha. In some embodiments, X3is a residue of Npg. In some embodiments, X3is a residue of Leu. In some embodiments, X3is a residue of Cha. In some embodiments, X3is a residue of Val. In some embodiments, X3is a residue of nLeu. In some embodiments, X3is a residue of Ile. In some embodiments, X3is a residue of CypA. In some embodiments, X3is a residue of CyLeu. In some embodiments, X3is a residue of Chg. In some embodiments, X3is a residue of DiethA. In some embodiments, X3is a residue of Ala. In some embodiments, X3is a residue of Aib. In some embodiments, X3is a residue of OctG. In some embodiments, X3is a residue of Cba. In some embodiments, X4is residue of an amino acid suitable for stapling. In some embodiments, X4is a residue of an amino acid which comprises two functional groups suitable for stapling. In some embodiments, X4is a residue of an amino acid which comprises two olefins, e.g., two terminal olefins. In some embodiments, X4is stapled. In some embodiments, X4is stapled with X1and / or X11. In some embodiments, X4is B5. In some embodiments, X4is R5. In some embodiments, X4is R4. In some embodiments, X4is R6. In some embodiments, X4is S5. In some embodiments, X6is a residue of amino acid that comprises an acidic or polar group. In some embodiments, X6is a residue of amino acid whose side chain comprises an acidic group, e.g., a −COOH group or a salt form thereof. In some embodiments, X6is a residue of 3COOHF, TfeGA, Asp, [CH2CMe2CO2H]TriAzDap, Glu, 2OH3COOHF, 4OH3COOHF, 4COOHF, 2COOHF, 5F3Me2COOHF, 4F3Me2COOHF, 5F3Me3COOHF, 4F3Me3COOHF, 3F2COOHF, or dGlu. In some embodiments, X6is a residue of 3COOHF, TfeGA, Asp, or [CH2CMe2CO2H]TriAzDap. In some embodiments, X6is a residue of 3COOHF. In some embodiments, X6is a residue of TfeGA. In some embodiments, X6is a residue of Asp. Insome embodiments, X6is a residue of Glu. In some embodiments, X7is a hydrophobic amino acid residue, e.g., those described for X3. In some embodiments, X7is a residue of an amino acid whose side chain is C1-10aliphatic optionally substituted with one or more non-polar and non-charged groups. In some embodiments, X7is a residue of Ala. In some embodiments, X7is a residue of Aib. In some embodiments, X7is a residue of nLeu. In some embodiments, X7is a residue of Cha. In some embodiments, X7is a residue of Npg. In some embodiments, X7is a residue of sAla. In some embodiments, X7is a residue of Val. In some embodiments, X7is a residue of CyLeu.. In some embodiments, X7is a residue of Leu. In some embodiments, X7is a residue of Cpg. In some embodiments, X7is a residue of Cbg. In some embodiments, X7is a residue of aMeL. In some embodiments, X7is a residue of DaMeL. In some embodiments, X7is a residue of aMeV. In some embodiments, X8is a hydrophobic amino acid residue, e.g., those described for X3. In some embodiments, X8is a residue of Ala. In some embodiments, X8is a residue of Aib. In some embodiments, X8is a residue of Cpg. In some embodiments, X8is a residue of Val. In some embodiments, X8is a residue of Leu. In some embodiments, X8is a residue of nLeu. In some embodiments, X8is a residue of Cba. In some embodiments, X9comprises a side chain comprising an optionally substituted aromatic group. In some embodiments, X9is an aromatic amino acid residue as described herein. In some embodiments, X9is Phe. In some embodiments, X9is 3COOHF. In some embodiments, X9is 2NapA. In some embodiments, X9is Tyr. In some embodiments, X9is 3Thi. In some embodiments, X9is 4FF. In some embodiments, X9is 4ClF. In some embodiments, X9is 4BrF. In some embodiments, X9is 3FF. In some embodiments, X9is 3ClF. In some embodiments, X9is 3BrF. In some embodiments, X9is 2FF. In some embodiments, X9is 3OMeF. In some embodiments, X9is 4CNF. In some embodiments, X9is 3CNF. In some embodiments, X9is 4MeF. In some embodiments, X9is 3MeF. In some embodiments, X10is a residue of an amino acid whose side chain comprises a polar group. In some embodiments, X10is Asn, Gln, Lys, etc. In some embodiments, X10is stapled. In some embodiments, X10is not stapled. In some embodiments, X10is stapled with X14. In some embodiments, a staple comprises −C(O)NH−. In some embodiments, X11is a residue of an amino acid suitable for stapling as described herein. In some embodiments, X11comprises −CH=CH2. In some embodiments, X11is a residue of PyrS2. In some embodiments, X11is Az3. In some embodiments, X11is PyrS1. In some embodiments, X12comprises a side chain comprising an optionally substituted aromatic group. In some embodiments, X12is an aromatic amino acid residue as described herein. In some embodiments, X12is a residue of an amino acid selected from Phe, 1NapA, 2cmbF, 2F3MeF, 2ClF, 2FurA, 2OMeF, 2MeF, 2BrF, 2CNF, 2NO2F, 2PyrA, 2Thi, 3PyrA, 3Thi, or 4PyrA. In some embodiments, X12is a residue of Phe. In some embodiments, X12is a residue of 2F3MeF. In some embodiments, X12is a residue of 2ClF. In some embodiments, X12is a residue of 2FurA. In some embodiments, X12is a residue of 2OMeF. In some embodiments, X12is a residue of 2MeF. In some embodiments, X12is a residue of 2BrF. In some embodiments, X12is a residue of 2CNF. In some embodiments, X12is a residue of 2NO2F. In some embodiments, X12is a residue of 2PyraA. In some embodiments, X12is a residue of 3PyrA. In some embodiments, X12is a residue of 3Thi. In some embodiments, X12is a residue of 4PyrA. In someembodiments, X12is a residue of His. In some embodiments, X12is a residue of 1NapA. In some embodiments, X12is a residue of 2Thi. In some embodiments, X12is a residue of 2cmbF. In some embodiments, X13comprises a side chain which is or comprises an optionally substituted aromatic group. In some embodiments, X13is an aromatic amino acid residue as described herein. In some embodiments, X13is a residue of BztA, 34ClF, 3Thi, Phe, 34MeF, 3BrF, 7FBztA, 2BrF, 3F3MeF, 4F3MeF, RbMe2NapA, RbMeBzta, SbMeBzta, 5IndA, 7ClBztA, 7MeBztA, 2ClF, 3ClF, 4BrF, 4ClF, or 3MeF. In some embodiments, X13is BztA. In some embodiments, X13is 34ClF. In some embodiments, X13is 3Thi. In some embodiments, X13is Phe. In some embodiments, X14is an amino acid residue suitable for stapling. In some embodiments, X14is stapled. In some embodiments, X14is stapled with X10as described herein. In some embodiments, X14is stapled with X7as described herein. In some embodiments, X14is GlnR, Lys, sAla, Gln, Cys, TriAzLys, AsnR, hGlnR, 4PipA, sAbu, Orn, dGlnR, [4mampiperidine]GlnR, [39N2spiroundecane]GlnR, [29N2spiroundecane]GlnR, iPrLys, sCH2S, [diaminobutane]GlnR, or [4aminopiperidine]GlnR. In some embodiments, X14is GlnR. In some embodiments, X14is Lys. In some embodiments, X14is sAla. In some embodiments, X14is Gln. In some embodiments, X14is Cys. In some embodiments, X14is TriAzLys. In some embodiments, X14is AsnR. In some embodiments, X14is hGlnR. In some embodiments, X14is 4PipA. In some embodiments, X14is sAbu. In some embodiments, X14is Orn. In some embodiments, X14is dGlnR. In some embodiments, X14is [4mampiperidine]GlnR. In some embodiments, X14is [39N2spiroundecane]GlnR. In some embodiments, X14is [29N2spiroundecane]GlnR. In some embodiments, X14is iPrLys. In some embodiments, X14is sCH2S. In some embodiments, X14is [diaminobutane]GlnR. In some embodiments, X14is [4aminopiperidine]GlnR. In some embodiments, X14is a C-terminus amino acid residue. In some embodiments, p15 is 1. In some embodiments, p15 is 0. In some embodiments, X15is a residue of Ala, Leu, Val, Aib, MorphNva, Thr, dAla, dLeu, [BiotinPEG8]Lys, Glu, or AzLys. In some embodiments, p16 is 1. In some embodiments, p16 is 0. In some embodiments, p17 is 1. In some embodiments, p17 is 0. In some embodiments, p18 is 1. In some embodiments, p18 is 0. In some embodiments, p19 is 1. In some embodiments, p19 is 0. In some embodiments, p20 is 1. In some embodiments, p20 is 0. In some embodiments, p21 is 1. In some embodiments, p21 is 0. In some embodiments, p22 is 1. In some embodiments, p22 is 0. In some embodiments, p23 is 1. In some embodiments, p23 is 0.

[0214] In some embodiments, an agent is or comprises a peptide having the structure of: RN−[X]p−[X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17−[X]p’−RC, or a salt thereof, wherein: each X is independently an amino acid residue; each p and p’ is independently 0-10; RNis independently a peptide, an amino protecting group or R’−LRN−; RCis independently 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 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 −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 atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms.

[0215] In some embodiments, p is 0. In some embodiments, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9. In some embodiments, p is 10.

[0216] In some embodiments, p’ is 0. In some embodiments, p’ is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p’ is 1. In some embodiments, p’ is 2. In some embodiments, p’ is 3. In some embodiments, p’ is 4. In some embodiments, p’ is 5. In some embodiments, p’ is 6. In some embodiments, p’ is 7. In some embodiments, p’ is 8. In some embodiments, p’ is 9. In some embodiments, p’ is 10.

[0217] In some embodiments, RNis an N-terminus capping group. In some embodiments, RNis −C(O)R, wherein R is as described herein. In some 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 methyl. In some embodiments, RNis Ac. In some embodiments, RNis a group suitable for stapling, or is stapled. In some embodiments, RNis 4pentenyl. In some embodiments, RNis 5hexenyl. In some embodiments, RNis BzAm2OAllyl. In some embodiments, RNis Ac, NPyroR3, 5hexenyl, 4pentenyl, Bua, C3a, Cpc, Cbc, CypCO, Bnc, CF3CO, 2PyCypCO, 4THPCO, Isobutyryl, Ts, 15PyraPy, 2PyBu, 4PymCO, 4PyPrpc, 3IAPAc, 4MePipzPrpC, MePipAc, MeImid4SO2, BzAm2OAllyl, Hex, 2PyzCO, 3Phc3,MeOPr, lithocholate, 2FPhc, PhC, MeSO2, Isovaleryl, EtHNCO, TzPyr, 8IAP, 3PydCO, 2PymCO, 5PymCO, 1Imidac, 2F2PyAc, 2IAPAc, 124TriPr, 6QuiAc, 3PyAc, 123TriAc, 1PyrazoleAc, 3PyPrpc, 5PymAc, 1PydoneAc, 124TriAc, Me2NAc, 8QuiSO2, mPEG4, mPEG8, mPEG16 or mPEG24.

[0218] In some embodiments, RCis a C-terminus capping group. In some embodiments, RCcomprises a PEG moiety. In some embodiments, RCis −O−LRC−R’ wherein each of LRCand R’ is independently as described herein. In some embodiments, RCis −OR’, wherein R’ is optionally substituted C1-C10aliphatic. In some embodiments, RCis −OR’, wherein R’ is optionally substituted C1-C10alkyl. In some embodiments, RCis −OR’, wherein R’ is optionally substituted C1-30heteroaliphatic having 1-10 heteroatoms. In some embodiments, RCis −LRC−R’, wherein one or more methylene unit of LRCare replaced with −O− and R’ is as described herein. In some embodiments, RCis −O−LRC−R’, wherein LRCis optionally substituted C1–6alkylene and R’ is as described herein. In some embodiments, RCis −O−LRC−R’, wherein LRCis optionally substituted C1–6alkylene and R’ is an optionally substituted group selected from C6-30aryl and 5-30 membered heteroaryl having 1-10 heteroatoms. In some embodiments, RCis −OR’ wherein R’ is optionally substituted C6-30arylaliphatic. In some embodiments, RCis −N(R’)2wherein each R’ is independently as described herein. In some embodiments, RCis −NHR’ wherein R’ is as described herein. In some embodiments, RCis −N(R)2wherein each R is independently as described herein. In some embodiments, RCis −NHR wherein R is as described herein. In some 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 methyl. In some embodiments, R is ethyl. In some embodiments, RCis −NH2. In some embodiments, RCis −NHEt.

[0219] In some embodiments, RCis −NHC(CH3)CH2OH. In some embodiments, RCis −(S)−NHC(CH3)CH2OH. In some embodiments, RCis −(R)−NHC(CH3)CH2OH. In some embodiments, RCisCIn some embodiments, R is. In some embodiments, RCis. In some embodiments, RCisCIn some embodiments, R is

[0220] In some embodiments, RCis −Alaol, wherein the amino group of −Alaol is bonded to the last −C(O)− of the peptide backbone (RCisCIn some embodiments, R is −dAlaol, wherein the amino group of −dAlaol is bonded to the last −C(O)− of the peptide backbone (RCisIn some embodiments, RCis −Prool, wherein the amino group of −Prool is bonded to the last −C(O)− of the peptidebackbone (RCisIn some embodiments, RCis −Throl, wherein the amino group of −Throl is bonded to the last −C(O)− of the peptide backbone (RCisCIn some embodiments, R is −Serol, wherein the amino group of −Serol is bonded to the last −C(O)− of the peptide backbone (RCis

[0221] In some embodiments, RCis −OH.

[0222] In some embodiments, an agent is or comprises a peptide analog. In some embodiments, an agent is or comprises an analog of a peptide described herein or a portion thereof. In some embodiments, an agent is or comprises an analog of a peptide described herein. In some embodiments, in a peptide analog, one or more of amino (e.g., −NH−), carbonyl or amide group (e.g., −C(O)NH−) are independently replaced with LReach of which is independently L as described herein. In some embodiments, in an analog of a peptide, one or more of backbone amino, carbonyl or amide group are independently replaced with LRas described herein. In some embodiments, LRis a bivalent moiety with a length of 0, 1, 2, 3, 4, or 5 atoms between its two covalent bonds (e.g., for −CH2−, one atom (one carbon atom between the two covalent bonds); for −CH2CH2−, two atoms (two carbon atoms between the two covalent bonds), etc.). In some embodiments, a length is 1 atom. In some embodiments, a length is 2 atoms. In some embodiments, a length is 3 atoms. In some embodiments, a length is 4 atoms. In some embodiments, a length is 5 atoms. In some embodiments, the length of LR(or L, or any moiety that can be L), measured by the number of atoms between its two covalent bonds, are the same as, or no more than about 1 or 2 atoms longer or shorter than, a group it replaces. In some embodiments, the length of LR(or L, or any moiety that can be L), measured by the number of atoms between its two covalent bonds, are the same as a group it replaces. In some embodiments, LRis a covalent bond. In some embodiments, LRis optionally substituted −CH2−. In some embodiments, LRis optionally substituted −CH2−CH2−. In some embodiments, LRis optionally substituted −CHR’−CHR’−. In some embodiments, LRis optionally substituted −C(R’)2−C(R’)2−. In some embodiments, LRis optionally substituted −CH=CH−. In some embodiments, LRis −C(R’)=C(R’)−. In some embodiments, L is LRas described herein. In some embodiments, an amino group is replaced with a covalent bond. In some embodiments, an amino group is replaced with optionally substituted −CH2−. In some embodiments, a carbonyl group is replaced with a covalent bond. In some embodiments, a carbonyl group is replaced with optionally substituted −CH2−. In some embodiments, an amide group is replaced with a covalent bond. In some embodiments, an amide group is replaced with optionally substituted −CH2−. In some embodiments, an amide group is replaced with optionally substituted −CH2−CH2−. In some embodiments, an amide groupis replaced with −C(R’)2−C(R’)2−. In some embodiments, an amide group is replaced with optionally substituted −CHR’−CHR’−. In some embodiments, an amide group is replaced with optionally substituted −CH=CH−. In some embodiments, an amide group is replaced with −C(R’)=C(R’)−. Amino Acids

[0223] As appreciated by those skilled in the art, various amino acids may be utilized in accordance with the present disclosure. For example, both naturally occurring and non-naturally occurring amino acids can be utilized in accordance with the present disclosure. In some embodiments, an amino acid is a compound comprising an amino group that can form an amide group with a carboxyl group and a carboxyl group. In some embodiments, an amino acid is an alpha amino acid. In some embodiments, an amino acid is a beta- amino acid. In some embodiments, an amino acid is a D-amino acid. In some embodiments, an amino acid is a L-amino acid. In some embodiments, an amino acid is an naturally encoded amino acid, e.g., in mammalian cells.

[0224] In some embodiments, an amino acid is a compound having the structure of formula A-I: N(Ra1)2−La1−C(Ra2)(Ra3)−La2−COOH, A-I or a salt thereof, wherein: each of Ra1, Ra2, Ra3is independently −La−R’; each of La, La1and La2is 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 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 −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 withtheir 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.

[0225] In some embodiments, a compound having the structure of formula A-I or a salt thereof has the structure of NH(Ra1)−La1−C(Ra2)(Ra3)−La2−COOH or a salt thereof.

[0226] In some embodiments, a ring moiety of, e.g., −Cy−, R (including those formed by R groups taken together), etc. is monocyclic. In some embodiments, a ring moiety is bicyclic or polycyclic. In some embodiments, a monocyclic ring is an optionally substituted 3-10 (3, 4, 5, 6, 7, 8, 9, or 10, 3-8, 3-7, 4-7, 4-6, 5-6, etc.) membered, saturated, partially unsaturated or aromatic ring having 0-5 heteroatoms. In some embodiments, each monocyclic ring unit of a bicyclic or polycyclic ring moiety is independently an optionally substituted 3-10 (3, 4, 5, 6, 7, 8, 9, or 10, 3-8, 3-7, 4-7, 4-6, 5-6, etc.) membered, saturated, partially unsaturated or aromatic ring having 0-5 heteroatoms.

[0227] In some embodiments, each heteroatom is independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, each heteroatom is independently selected from oxygen, nitrogen, and sulfur.

[0228] In some embodiments, La1is a covalent bond. In some embodiments, a compound of formula A- 1 is of the structure NH(Ra1)−C(Ra2)(Ra3)−La2−COOH.

[0229] In some embodiments, La2is a covalent bond. In some embodiments, a compound of formula A- 1 is of the structure NH(Ra1)−C(Ra2)(Ra3)−La2−COOH.

[0230] In some embodiments, La1is a covalent bond and La2is a covalent bond. In some embodiments, a compound of formula A-1 is of the structure NH(Ra1)−C(Ra2)(Ra3)−COOH.

[0231] In some embodiments, an amino acid is suitable for stapling. In some embodiments, an amino acid comprises a terminal olefin. Certain such amino acids are exemplified herein (e.g., those described in or utilized in peptides of various Tables).

[0232] In some embodiments, an agent comprises a detectable moiety, which can either be detected directly or indirectly. For example, in some embodiments, a detectable moiety is or comprises a fluorescent group. In some embodiments, a detectable moiety is or comprises a biotin moiety. In some embodiments, a detectable moiety is connected to the rest of an agent at an amino acid residue, e.g., through a side chain, optionally through a linker (e.g., L as described herein). In some embodiments, a detectable moiety is −N3, which may be detected after a click chemistry reaction with a labeled agent comprising an alkyne.

[0233] In some embodiments, the present disclosure provides various compounds, which among other things may be utilized as amino acids for a number of applications, e.g., for preparation of peptides or other useful compounds.

[0234] In some embodiments, a compound (e.g., an amino acid or a protected and / or activated form thereof) or a salt thereof comprises 1) a first group which is an optionally protected amino group, 2) a second group which is an optionally protected and / or activated carboxyl group, and 3) a side chain (typically bonded to an atom between the first and second groups (“a side chain attachment atom”)) which comprises anoptionally protected and / or activated carboxyl group and a) an optionally substituted ring (which ring is typically between the optionally protected and / or activated carboxyl group of the side chain and a side chain attachment atom) or b) an amino group (which amino group is typically between the optionally protected and / or activated carboxyl group of the side chain and a side chain attachment atom). In some embodiments, a provided compound is an optionally protected and / or activated amino acid or a salt thereof, wherein the side chain of the amino acid comprises an optionally protected and / or activated carboxyl group, and an optionally substituted ring or an amino group, wherein the optionally substituted ring or an amino group is between the optionally protected and / or activated carboxyl group and a backbone atom to which a side chain is attached (e.g., an atom between an amino and carboxyl group, both of which can be optionally and independently protected and / or activated (e.g., an alpha carbon atom in an amino acid)).

[0235] In some embodiments, the present disclosure provides compounds having the structure of formula PA: N(RPA)(Ra1)−La1−C(Ra2)(Ra3)−La2−C(O)RPC, PA or a salt thereof, wherein: RPAis −H or an amino protecting group; each of Ra1and Ra3is independently −La−R’; Ra2is −Laa−C(O)RPS; each of La, La1and La2is independently L; −C(O)RPSis optionally protected or activated −COOH; −C(O)RPCis optionally protected or activated −COOH; 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 −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, monocyclic, bicyclic or polycyclic ring having, inaddition 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 atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms.

[0236] In some embodiments, an amino acid is described in WO 2022 / 261257, the amino acids of which are incorporated herein by reference.

[0237] As described above, 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−.

[0238] In some embodiments, L is a covalent bond.

[0239] In some embodiments, L (or La, Laa, La1, La2, Ls1, Ls2, Ls3, or another variable or moiety that can be L, or a linker moiety) is an optionally substituted, bivalent C1-C25, C1-C20, C1-C15, C1-C10, C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, or C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, or C20, aliphatic 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−.

[0240] In some embodiments, L, La, Laa, La1, La2, Ls1, Ls2, Ls3, L”, or another variable or moiety that can be L, or a linker moiety, is an optionally substituted, bivalent C1-C25, C1-C20, C1-C15, C1-C10, C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, or C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, or C20, aliphatic 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−. In some embodiments, it is an optionally substituted, bivalent C1-C10, C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, or C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10, aliphatic 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−. In some embodiments, it is an optionally substituted, bivalent C2aliphatic 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−. In some embodiments, it is an optionally substituted, bivalent C3aliphatic 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−. In some embodiments, it is an optionally substituted, bivalent C4aliphatic 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−. In some embodiments, it is an optionally substituted, bivalent C5aliphatic 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−. In some embodiments, it is an optionally substituted, bivalent C6aliphatic 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−. In some embodiments, the bivalent aliphatic is saturated. In some embodiments, the bivalent aliphatic is linear. In some embodiments, the bivalent aliphatic is branched. In some embodiments, it is an optionally substituted, bivalent linear saturated C6aliphatic 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−. In some embodiments, each replacement if any is independently with −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, each replacement if any is independently with −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, each replacement if any is independently with −O−, −S−, −N(R’)−, −C(O)−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−. In some embodiments, each replacement if any is independently with −O−, −S−, −N(R’)−, or −C(O)−. In some embodiments, L, La, Laa, La1, La2, Ls1, Ls2, Ls3, L”, or another variable or moiety that can be L, or a linker moiety, is an optionally substituted, bivalent C1-C6linear saturated aliphatic wherein one or more methylene units is optionally and independently replaced with −O−, −S−, −N(R’)−, or −C(O)−. In some embodiments, it is an optionally substituted, bivalent C1-C5linear saturated aliphatic wherein one or more methylene units is optionally and independently replaced with −O−, −S−, −N(R’)−, or −C(O)−. In some embodiments, it is an optionally substituted, bivalent C1-C4linear saturated aliphatic wherein one or more methylene units is optionally and independently replaced with −O−, −S−, −N(R’)−, or −C(O)−. In some embodiments, it is an optionally substituted, bivalent C1-C3linear saturated aliphatic wherein one or more methylene units is optionally and independently replaced with −O−, −S−, −N(R’)−, or −C(O)−. In some embodiments, it is an optionally substituted, bivalent C1-C2linear saturated aliphatic wherein one or more methylene units is optionally and independently replaced with −O−, −S−, −N(R’)−, or −C(O)−. In some embodiments, it is a bivalent C1-C6linear saturated aliphatic wherein one or more methylene units is optionally and independently replaced with −O−, −S−, −N(R’)−, or −C(O)−. In some embodiments, it is a bivalent C1-C5linear saturatedaliphatic wherein one or more methylene units is optionally and independently replaced with −O−, −S−, −N(R’)−, or −C(O)−. In some embodiments, it is a bivalent C1-C4linear saturated aliphatic wherein one or more methylene units is optionally and independently replaced with −O−, −S−, −N(R’)−, or −C(O)−. In some embodiments, it is a bivalent C1-C3linear saturated aliphatic wherein one or more methylene units is optionally and independently replaced with −O−, −S−, −N(R’)−, or −C(O)−. In some embodiments, it is a bivalent C1-C2linear saturated aliphatic wherein one or more methylene units is optionally and independently replaced with −O−, −S−, −N(R’)−, or −C(O)−. In some embodiments, there is no replacement of methylene unit. In some embodiments, there is one replacement. In some embodiments, there is two replacement. In some embodiments, there is three replacement. In some embodiments, there is four or more replacement. In some embodiments, R’ in each moiety that is utilized to replace a methylene unit (e.g., −N(R’)−) as described herein is hydrogen or optionally substituted C1–6aliphatic or phenyl. In some embodiments, R’ is each such moiety is hydrogen or optionally substituted C1–6alkyl. In some embodiments, R’ is each such moiety is hydrogen or C1–6alkyl. In some embodiments, each −Cy− is optionally substituted bivalent ring selected from 3-10, 3-9, 3-8, 3-7, 5-10, 5-9, 5-8, 5-7, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10 membered cycloaliphatic and heterocyclylene having 1-3 heteroatoms, phenylene, and 5-6 membered heteroarylene having 1-3 heteroatoms. In some embodiments, −Cy− is optionally substituted bivalent 3-10, 3-9, 3-8, 3-7, 5-10, 5-9, 5- 8, 5-7, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10 membered cycloaliphatic. In some embodiments, −Cy− is optionally substituted 3-10, 3-9, 3-8, 3-7, 5-10, 5-9, 5-8, 5-7, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10 membered heterocyclylene having 1-3 heteroatoms. In some embodiments, −Cy− is optionally substituted 3-10, 3-9, 3-8, 3-7, 5-10, 5-9, 5-8, 5-7, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10 membered heterocyclylene having 1 heteroatom. In some embodiments, −Cy− is optionally substituted phenylene. In some embodiments, −Cy− is phenylene. In some embodiments, −Cy− is optionally substituted 5-6 membered heteroarylene having 1-3 heteroatoms. In some embodiments, −Cy− is optionally substituted 5-6 membered heteroarylene having 1 heteroatom. In some embodiments, a heteroatom is nitrogen. In some embodiments, a heteroatom is oxygen. In some embodiments, a heteroatom is sulfur. In some embodiments, L, La, Laa, La1, La2, Ls1, Ls2, Ls3, L”, or another variable or moiety that can be L, or a linker moiety, is optionally substituted −(CH2)n−. In some embodiments, it is −(CH2)n−. 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, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.

[0241] In some embodiments, L, La, Laa, La1, La2, Ls1, Ls2, Ls3, L”, or another variable or moiety that can be L, or a linker moiety, is an optionally substituted, bivalent 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−.

[0242] Those skilled in the art appreciate that embodiments described for one linker moiety that can beL or L” (e.g., Laa, Ls1, Ls2, Ls3, Ls, La, La1, La2, LRN, etc.) may also be utilized for another group that can be L or L” to the extent that such embodiments fall within the definition of L or L”.

[0243] As described above, each R’ is independently −R, −C(O)R, −CO2R, or −SO2R. In some embodiments, R’ is −La−R. In some embodiments, R’ is R. In some embodiments, R’ is −C(O)R. In some embodiments, R’ is −CO2R. In some embodiments, R’ is −SO2R. In some embodiments, R’ is −H.

[0244] As described above, 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 atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms.

[0245] As described herein, in some embodiments, R is −H. In some embodiments, R is not −H. In some embodiments, R is optionally substituted C1-10aliphatic. In some embodiments, R is optionally substituted C1-10alkyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is isopropyl. In some embodiments, R is −CF3. In some embodiments, R is −CH2CF3. In some embodiments, R is butyl. In some embodiments, R is t-butyl. In some embodiments, R is optionally substituted C3-10cycloaliphatic. In some embodiments, R is optionally substituted C3-10cycloalkyl. In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments, R is optionally substituted cyclopentyl. In some embodiments, R is optionally substituted cyclohexyl. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is optionally substituted 5-membered heteroaryl having 1-3 heteroatoms. In some embodiments, R is optionally substituted 5-membered heteroaryl having 1 heteroatom. In some embodiments, R is optionally substituted 6-membered heteroaryl having 1-3 heteroatoms. In some embodiments, R is optionally substituted 6-membered heteroaryl having 1 heteroatom. In some embodiments, R is optionally substituted bicyclic 8-10 membered aromatic ring having 0-5 heteroatoms. In some embodiments, R is optionally substituted bicyclic 9-membered aromatic ring having 1- 5 heteroatoms. In some embodiments, R is optionally substituted bicyclic 10-membered aromatic ring having 1-5 heteroatoms. In some embodiments, R is optionally substituted bicyclic 9-membered aromatic ring having 1 heteroatom. In some embodiments, R is optionally substituted bicyclic 10-membered aromatic ring having 1 heteroatom. In some embodiments, R is optionally substituted bicyclic 10-membered aromatic ring having no heteroatom. In some embodiments, R is optionally substituted 3-10 membered heterocyclyl having1-5 heteroatoms. In some embodiments, R is optionally substituted 5-14 membered bicyclic heterocyclyl having 1-5 heteroatoms.

[0246] In some embodiments, two R groups (or two groups that can be R, e.g., two groups each independently selected from R’, Ra1, Ra2, Ra3, Ra5, RRN, etc.) are 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 atom, 0-10 heteroatoms. In some embodiments, a formed ring is substituted. In some embodiments, a formed ring is unsubstituted. In some embodiments, a formed ring is 3-30, 3-20, 3-15, 3-10, 3-9, 3-8, 3-7, 3- 6, 4-10, 4-9, 4-8, 4-7, 4-6, 5-10, 5-9, 5-8, 5-7, 5-6, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 membered. In some embodiments, a formed ring is 3-10 membered. In some embodiments, a formed ring is 3-7 membered. In some embodiments, a formed ring is 4-10 membered. In some embodiments, a formed ring is 4-7 membered. In some embodiments, a formed ring is 5-10 membered. In some embodiments, a formed ring is 5-7 membered. 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. In some embodiments, a formed ring is 7-membered. In some embodiments, a formed ring is 8-membered. In some embodiments, a formed ring is 9-membered. In some embodiments, a formed ring is 10-membered. In some embodiments, a formed ring is monocyclic. In some embodiments, a formed ring is bicyclic. In some embodiments, a formed ring is polycyclic. In some embodiments, a formed ring has no heteroatoms in addition to the intervening atom(s). In some embodiments, a formed ring has 1-10, e.g., 1-5, 1-3, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 heteroatoms in addition to the intervening atom(s). In some embodiments, a formed ring is saturated. In some embodiments, a formed ring is partially unsaturated. In some embodiments, a formed ring comprises one or more aromatic ring. In some embodiments, a formed ring is bicyclic or polycyclic, and each monocyclic unit is independently 3-10 membered, saturated, partially unsaturated or aromatic and having 0-5 heteroatoms. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur.

[0247] In some embodiments, a group that can be R, e.g., R’, Ra1, Ra2, Ra3, Ra5, RRN, etc., is R as described herein. Those skilled in the art appreciate that embodiments described for one group that can be R may also be utilized for another group that can be R to the extent that such embodiments fall within the definition of R.

[0248] In some embodiments, as used in the present disclosure, e.g., in various embodiments or R, R’, various formulae, etc., each heteroatom is independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, each heteroatom is independently selected from oxygen, nitrogen and sulfur. In some embodiments, in provided compound each heteroatom of heteroaryl, heterocyclyl, heteroaliphatic, ring (e.g., −Cy−, ring formed by groups taken together (e.g., two R groups taken together) with their intervening atom(s) (if any), etc.), etc., is independently selected from nitrogen, oxygen and sulfur. In some embodiments, in provided compound each heteroatom is independently selected from nitrogen,oxygen, sulfur, silicon and phosphorus. In some embodiments, rings (e.g., cycloaliphatic, aryl, heteroaryl, heterocyclyl, etc. in variables (e.g., R, R’ etc.), formulae, etc.) contain 1-30 (e.g., 2-30, 1-20, 2-20, 1-15, 2-15, 1-10, 2-10, 1-6, 2-6, etc.) ring carbon atoms and 0-15 (e.g., 0, 1-15, 0-10, 0-5, 1-10, 1-5, etc.) ring heteroatoms. In some embodiments, rings contain 1-20 ring carbon atoms and 0-10 ring heteroatoms. In some embodiments, rings contain 2-20 ring carbon atoms and 0-10 ring heteroatoms. In some embodiments, rings contain 1-10 ring carbon atoms and 0-5 ring heteroatoms. In some embodiments, rings contain 2-10 ring carbon atoms and 0-5 ring heteroatoms. In some embodiments, rings contain 2-10 ring carbon atoms and 0-5 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, rings formed by groups taken together (e.g., two R groups taken together) contain, in addition to the intervening atom(s) of such groups, 1-20 (e.g., 1-15, 1-10, 1-5, etc.) additional ring carbon atoms and 0-10 (e.g., 0, 1-10, 0-5, 1-5, etc.) additional ring heteroatoms. In some embodiments, such rings contain 1-15 additional ring carbon atoms and 0-5 ring heteroatoms. In some embodiments, such rings contain 1-10 additional ring carbon atoms and 0-5 ring heteroatoms. In some embodiments, each ring heteroatom is independently selected from nitrogen, oxygen and sulfur. As described herein, various groups may be optionally substituted. Substituents are routinely utilized in chemistry including in development of various therapeutics. Many substituents can be utilized in accordance with the present disclosure. In some embodiments, a substituent is a hydrocarbon group. In some embodiments, a substituent comprises a heteroatom. In some embodiments, a substituent comprises multiple heteroatoms. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, sulfur, phosphorus and silicon. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, and sulfur. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, fluorine, chlorine, bromine, iodine, nitrogen, oxygen, and sulfur. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in a substituent is about or no more than about 1; in some embodiments, it is no more than about 2; in some embodiments, it is no more than about 3; in some embodiments, it is no more than about 4; in some embodiments, it is no more than about 5; in some embodiments, it is no more than about 6; in some embodiments, it is no more than about 7; in some embodiments, it is no more than about 8; in some embodiments, it is no more than about 9; in some embodiments, it is no more than about 10; in some embodiments, it is no more than about 11; in some embodiments, it is no more than about 12; in some embodiments, it is no more than about 13; in some embodiments, it is no more than about 14; in some embodiments, it is no more than about 15; in some embodiments, it is no more than about 20. In some embodiments, the total number of carbon and non- halogen heteroatom(s) in each substituent is independently no more than about 20. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 15. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 10. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 6.

[0249] Certain amino acids and structure moieties are described in WO 2022 / 020651, WO 2022 / 020652, and WO 2022 / 261257, the amino acids and structure moieties of each of which are independently incorporated herein by reference, and can be utilized in accordance with the present disclosure.

[0250] In some embodiments, an amino acid, or a structure moiety, of an amino acid or an agent (e.g., a peptide), is selected from below. A N-terminal cap (N-Term) is connected via R1to the amino group (R1) of the first amino acid (AA1). In some embodiments, a N-Term cap may be properly considered as part of AA1. From there, each carboxylate (R2) of that amino acid is connected to the amino group (R1) of the subsequent amino acid, until the carboxylate (R2) of the final amino acid is connected to R1of a C-terminal group. For any amino acid that has a branch point (R3) and a branching monomer is indicated in brackets, R1of the monomer in brackets is attached to R3of the amino acid. Unless otherwise noted, for the amino acid Dap, with two potential branch points (R3and R4), if two branches are indicated, the R1of the first branch is connected to R3, and R1of the second branch connected to R4; in some embodiments, only one branch is indicated and R4 is −H. For any pair of amino acids that terminate in a *3 designation, the R3groups of each of those amino acids are linked to each other. Likewise, for any pair of amino acids that terminate in a **3 designation, the R3groups of those amino acids are linked to each other. For any sequence that contains a pair of branching amino acids with R3groups, and one contains a branching monomer that contains both R1and R2groups, then R1is attached to the branching amino acid adjacent to it in the sequence, and the R2group of the branching monomer is attached to R3of the amino acid with no branching monomer designated. For example, in various peptides that have one of Cys, hCys, Pen, or aMeC at position 10 and also one of Cys, hCys, Pen, or aMeC at position 14, and a branching group off of the amino acid residue 10, the R1of that branching group is tied to the R3of the amino acid residue at position 10, while the R2of that branching group is tied to the R3of the amino acid residue at position 14. For any amino acid which has a branching amino acid containing R3and nothing attached to it by the above, then R3= H. Typically, all residues with terminal olefins are linked (stapled) by ring-closing metathesis. Certain examples are provided in Table E2 and Table E3. In some embodiments, the present disclosure provides agents, e.g., peptides such as stapled peptides, comprising one or more amino acid residues selected from below.

[0251] Table A-IV. Certain useful compounds or moieties.Table A-IV (Continued; certain moieties may be presented in []) Certain moieties useful as, e.g., Lys analogs, branch point amino acid residues, or non-RCM stapling amino acid residuesCertain moieties useful as, e.g., stapling amino acid residues (e.g., RCM for other stapling technologies)Certain moieties useful as, e.g., aromatic amino acid residuesCertain moieties useful as amino acid residuesCertain moieties useful as, e.g., amino acid residues (e.g., D-amino acid residues, homologated amino acid residues, alkyl (e.g., methyl) amino acid residues, etc.)Certain moieties useful as, e.g., amino acid residues (e.g., alkyl amino acid residues, hydrophobic amino acid residues, etc.)Certain moieties useful as, e.g., amino acid residues (e.g., polar amino acid residues, basic amino acid residues, etc.)Certain moieties useful as, e.g., amino acid residues (e.g., acidic amino acid residues, non-aromatic amino acid residues, etc.)Certain moieties (e.g., moieties utilized in [] in various agents)Certain moieties (e.g., moieties utilized in [] in various agents, amino acid residues, etc.)

[0252] In some embodiments, within a bracket there are two moieties, e.g., [Ac-dPEG2], typically R1of the first is connected to R1of the latter. For example, in [Ac-dPEG2], R1of Ac is connected to R1of dPEG2. R2of dPEG2 can be connected to other moieties, e.g., in [Ac-dPEG2]-Lys, R3of Lys.

[0253] In some embodiments, the present disclosure provides an agent, e.g., a peptide agent (in various embodiments, a stapled peptide agent), comprising a moiety selected from the table above. In some embodiments, a residue is stapled, e.g., forming a staple with another moiety. In some embodiments, an agent comprises a staple formed between two moieties each independently selected from the table above. In some embodiments, a staple comprises a double bond. In some embodiments, a staple comprises an E double bond. In some embodiments, a staple comprises a Z double bond. In some embodiments, a double bond is converted into another moiety, e.g., to a saturated bond through hydrogenation, an epoxide through epoxidation, etc. In some embodiments, a moiety, e.g., an amino acid residue, comprises two groups that can be utilized for stapling. In some embodiments, an amino acid residue comprises two groups for stapling, e.g., B3, B4, B5, B6, Dap7Gly, Dap7Pent, DapAc7EDA, DapAc7PDA, Dap7Abu, etc. In some embodiments, a N-terminal group, e.g., 4pentenyl, 5hexenyl, etc., may be considered as part of the first amino acid residue for stapling. In some embodiments, amino acid residues with N-terminal groups (e.g., 4pentenyl, 5hexenyl, etc.) such as 4pentenyl-PL3, 5hexenyl-PL3, etc., comprise two groups, e.g., two double bonds, for stapling. In some embodiments, a group for stapling is a double bond. In some embodiments, each group for stapling is independently a double bond. In some embodiments, a group for stapling is a double bond and the other is not (e.g., amino group, or a group which is or comprises R3). In some embodiments, an agent comprise one and no more than one residue comprising two or more residues for stapling. In some embodiments, an agent comprising one and no more than one amino acid residue that is bonded to two staples. In some embodiments, agents comprise staples having different types of structures and / or formed by different types oftransformations. For example, in some embodiments, an agent comprises a staple whose formation does not comprises an olefin metathesis transformation and / or modification of a carbon-carbon double bond (e.g., hydrogenation). In some embodiments, such agents may provide improved properties, activities, design flexibility, manufacturing efficiency, etc.

[0254] In some embodiments, a compound has a structure selected from the table above, wherein R1is −OH. In some embodiments, a compound has a structure selected from the table above, wherein R1is −H. In some embodiments, a compound is a compound has the structure selected from the table above, wherein R1is −H or amino protecting group (e.g., Fmoc, tBoc, etc.) and R2is −OH, a carboxyl protecting or activating group, or a salt thereof. In some embodiments, a compound is a compound has the structure selected from the table above, wherein R1is −H or amino protecting group and R2is −OH, or a salt thereof. In some embodiments, a compound is a compound has the structure selected from the table above, wherein R1is −H and R2is −OH, or a salt thereof. In some embodiments, a compound is a compound has the structure selected from the table above, wherein R1is −H, R2is −OH and R3is −H, or a salt thereof. In some embodiments, R3is −H or a protecting group. In some embodiments, R3is −H. In some embodiments, a compound has a structure selected from the table above, wherein R1is an amino protection group, e.g., Fmoc, tBoc, etc. In some embodiments, a compound has a structure selected from the table above, wherein R1is an amino protecting group, e.g., Fmoc, tBoc, etc., and R2is −OH, or −COR2is an optionally substituted, protected or activated carboxyl group. In some embodiments, R2is −OH. In some embodiments, an amino acid residue has a structure selected from the table above, wherein each of R1and R2independently represents a connection site (e.g., for structure, the residue is of the structureIn some embodiments, an agent, a peptide or a stapled peptide comprises such an amino acid residue.

[0255] Among other things, the present disclosure provides peptides, including stapled peptides, comprising residues of amino acids described herein. In some embodiments, the present disclosure provides various methods comprising utilizing amino acids, optionally protected and / or activated, as described herein. In some embodiments, the present disclosure provides methods for preparing peptides, comprising utilizing amino acids, typically protected and / or activated, as described herein. For example, in some embodiments, various amino groups are Fmoc protected for peptide synthesis (particularly for forming backbone peptide bonds). In some embodiments, various side chain carboxylic acid groups are t-Bu protected (−C(O)−O−tBu).

[0256] In some embodiments, an agent, e.g., a peptide, a stapled peptide, a stitched peptide, etc., is less than about 5000 Daltons in mass. In some embodiments, an agent is greater than or equal to about 900 Daltons and less than about 5000 Daltons in mass. In some embodiments, an agent is greater than or equal to about 1500 Daltons and less than about 5000 Daltons in mass. In some embodiments, an agent is greater than or equal to about 2000 Daltons and less than about 5000 Daltons in mass. In some embodiments, an agent isgreater than or equal to about 2500 Daltons and less than about 5000 Daltons in mass. In some embodiments, an agent is greater than or equal to about 1000 Daltons and less than about 3000 Daltons in mass. In some embodiments, an agent is greater than or equal to about 1500 Daltons and less than about 3000 Daltons in mass. In some embodiments, an agent is greater than or equal to about 1500 Daltons and less than about 2500 Daltons in mass. In some embodiments, an agent is greater than or equal to about 1600 Daltons and less than about 2200 Daltons in mass. In some embodiments, the agent is no more than about 900 Daltons in mass. In some embodiments, an agent is no more than about 500 Daltons in mass. In some embodiments, an agent is no more than about 300 Daltons in mass. In some embodiments, an agent is no more than about 200 Daltons in mass. Characterization

[0257] In some embodiments, agents, e.g., peptides, are characterized with respect to, for example, one or more characteristics such as binding characteristics – e.g., with respect to a particular target of interest (e.g., beta-catenin or a portion thereof), stability characteristics, for example in solution or in dried form, cell permeability characteristics, solubility, lipophilicity, etc.

[0258] In some embodiments, a binding characteristic may be or comprise specificity, affinity, on-rate, off-rate, etc, optionally under (or over a range of) specified conditions such as, for example, concentration, temperature, pH, cell type, presence or level of a particular competitor, etc.

[0259] As will be appreciated by those skilled in the art, assessments of characteristics as described herein may involve comparison with an appropriate reference (e.g., a positive or negative control) which may, in some embodiments, be a contemporaneous reference or, in some embodiments, a historical reference.

[0260] In some embodiments, desirable characteristics may be, for example: binding to a desired target (e.g., a dissociation constant (KD) of at least less than about 1 μM, and preferably a KDof less than about 50 nM); cell penetration (e.g., as measured by fluorescence-based assays or mass spectrometry of cellular fractions, etc.); solubility (e.g., soluble at less than about 1000 uM agent, or soluble at less than about 500 uM agent, or soluble at less than about 100 uM agent, or less than about 50 uM, or less than about 35 uM); activity (e.g., modulating one or more functions of a target, which may be assessed in a cellular reporter assay (e.g., with an IC50 of less than a concentration, e.g., less than about 1 μM, less than about 500 nM, less than about 50 nM, less than about 10 nM, etc.), an animal model (e.g., various animal models described in the Examples) and / or a subject; stability, which may be assessed using a number of assays (e.g., in a rat pharmacokinetic study (e.g., administered via oral, iv, ip, etc.) with a terminal half-life of greater than a suitable time, e.g., 1 hour); low toxicity, which might be assessed by a number of assays (e.g., a standard ADME / toxicity assays); and / or low levels of cytotoxicity (e.g., low levels of lactate dehydrogenase (LDH) released from cells when treated at a suitable concentration, e.g., about 10 μM of a peptide). In some embodiments, an agent of the invention comprises an affinity of less than about 10 nM, for example, an IC50 of 7 nM).

[0261] In some embodiments, provided agents can bind to targets, e.g., beta-catenin, with an EC 50 of no more than about 2000 nM. In some embodiments, an EC50 is no more than about 1500 nM. In some embodiments, an EC50 is no more than about 1000 nM. In some embodiments, an EC50 is no more than about 500 nM. In some embodiments, an EC50 is no more than about 300 nM. In some embodiments, an EC50 is no more than about 200 nM. In some embodiments, an EC50 is no more than about 100 nM. In some embodiments, an EC50 is no more than about 75 nM. In some embodiments, an EC50 is no more than about 50 nM. In some embodiments, an EC50 is no more than about 25 nM. In some embodiments, an EC50 is no more than about 10 nM. In some embodiments, an EC50 is no more than about 5 nM. In some embodiments, an EC50 is measured by fluorescence polarization as described in the Examples.

[0262] In some embodiments, the present disclosure provides agents, e.g., stapled peptides, with suitable solubility for various purposes. In some embodiments, solubility of provided agents, e.g., in PBS, is about or at least about 5-100 uM (e.g., about or at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, or 100 uM). In some embodiments, solubility is about or at least about 25 uM. In some embodiments, solubility is about or at least about 30 uM. In some embodiments, solubility is about or at least about 40 uM. In some embodiments, solubility is about or at least about 50 uM. In some embodiments, provided agents, e.g., stapled peptides, are protein bound in serum; in some embodiments, they are at least about 85%, 90%, or 95% protein bound in serum. In some embodiments, provided agents are over 95% protein bound in serum.

[0263] In some embodiments, provided agents can traverse a cell membrane of an animal cell. In some embodiments, provided agents can traverse a cell membrane of a human cell.

[0264] Among other things, provided agents can bind to motifs, residues, or polypeptides. In some embodiments, provided agents bind to beta-catenin. In some embodiments, a dissociation constant (KD) is about 1 nM to about 1 uM. In some embodiments, a KDis no more than about 1 uM. In some embodiments, a KDis no more than about 500 nM. In some embodiments, a KDis no more than about 250 nM. In some embodiments, a KDis no more than about 100 nM. In some embodiments, a KDis no more than about 50 nM. In some embodiments, a KDis no more than about 25 nM. In some embodiments, a KDis no more than about 10 nM. In some embodiments, a KDis no more than about 5 nM. In some embodiments, a KDis no more than about 1 nM. As appreciated by those skilled in the art, various technologies are available and can be utilized to measure KDin accordance with the present disclosure. In some embodiments, KDis measured by Surface Plasmon Resonance (SPR) as illustrated herein.

[0265] In some embodiments, provided agents binds to a polypeptide whose sequence is or comprising SEQ ID NO: 2, or a fragment thereof: SVLFYAITTLHNLLLHQEGAKMAVRLAGGLQKMVALLNKTNVKFLAITTDCLQILAYGNQESKLIIL ASGGPQALVNIMRTYTYEKLLWTTSRVLKVLSVCSSNKPAIVEAGGMQALGLHLTDPSQRLVQNCL WTLRNLSDAATKQEGMEGLLGTLVQLLGSDDINVVTCAAGILSNLTCNNYKNKMMVCQVGGIEAL VRT (SEQ ID NO: 2).

[0266] In some embodiments, provided agents have one or more or all of the following interactions withbeta-catenin: Direct interactions (), water mediated [], non-polar contacts {} LQIL{AY}(G){NQ}ES(K)LIILA (residue 301-317 of Uniprot P35222 sequence) (SEQ ID NO: 3) SRVL{(K)V}LS{V}CSSN (residue 341-353 of Uniprot P35222 sequence) (SEQ ID NO: 4) RLV{QN}C{L}(W)TL{R}(N)LSDA (residue 376-391 of Uniprot P35222 sequence) (SEQ ID NO: 5) LGSD[D]I(N){V}V{TC}AAGI (residue 409-423 of Uniprot P35222 sequence) (SEQ ID NO: 6)

[0267] In some embodiments, an agent, e.g., a 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, K345, V346, V349, Q379, N380, L382, W383, R386, N387, D413, N415, V416, T418, and C419. In some embodiments, an agent, e.g., a 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 seven of the following amino acid residues in SEQ ID NO: 1 at the indicated positions: G307, K312, K345, W383, R386, N387, D413, and N415. In some embodiments, an agent, e.g., a 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 seven of the following amino acid residues in SEQ ID NO: 1 at the indicated positions: G307, K312, K345, W383, N387, D413, and N415.

[0268] In some embodiments, provided agents interact with beta-catenin at one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8 or 9) of G307, K312, K345, Q379, L382, W383, N387, N415 and V416. In some embodiments, provided agents interact with beta-catenin at one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) of Y306, G307, K312, K345, Q379, L382, W383, N387, N415 and V416. In some embodiments, provided agents interact with beta-catenin at one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) of G307, K312, K345, Q379, L382, W383, R386, N387, N415 and V416. In some embodiments, provided agents interact with beta-catenin at one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11) of Y306, G307, K312, K345, Q379, L382, W383, R386, N387, N415 and V416. In some embodiments, provided agents interact with beta-catenin at one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) of Y306, G307, K312, K345, V349, Q379, L382, W383, R386, N387, N415 and V416. In some embodiments, provided agents interact with beta-catenin at one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) of G307, K312, K345, W383, R386, N387, D413 and N415. In some embodiments, provided agents interact with beta-catenin at one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) of G307, K312, K345, W383, N387, D413 and N415. In some embodiments, provided agents interact with beta- catenin at one or both of K312 and R386. In some embodiments, provided agents interact with G307. In some embodiments, provided agents interact with K312. In some embodiments, provided agents interact with beta-catenin at one or more of K345, W383, D413 and N415. In some embodiments, provided agents interact with beta-catenin at one or more of K345 and W383. In some embodiments, provided agents interactwith beta-catenin at one or more of D413 and N415. In some embodiments, provided agents interact with Y306. In some embodiments, provided agents interact with G307. In some embodiments, provided agents interact with K312. In some embodiments, provided agents interact with K345. In some embodiments, provided agents interact with V349. In some embodiments, provided agents interact with Q379. In some embodiments, provided agents interact with L382. In some embodiments, provided agents interact with W383. In some embodiments, provided agents interact with R386. In some embodiments, provided agents interact with N387. In some embodiments, provided agents interact with D413. In some embodiments, provided agents interact with N415. In some embodiments, provided agents interact with V416.

[0269] In some embodiments, provided agents interact with one or more of amino acid residues that are or correspond to K312, R386, K345 and W383 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 and R386 of SEQ ID NO: 1. In some embodiments, interaction with an amino acid residue can be assessed through mutation of such an amino acid residue (e.g., mutation of K, R, etc. to D, E, etc.).

[0270] As those skilled in the art reading the present disclosure will appreciate, in some embodiments, interactions with beta-catenin may be assessed by contacting an agent with either a full-length or a portion of beta-catenin. In some embodiments, a portion of beta-catenin comprises the interacting residues above. In some embodiments, a portion of beta-catenin is or comprises SEQ ID NO: 2. In some embodiments, a portion of beta-catenin is expressed with a tag (e.g., for purification, detection, etc.). In some embodiments, a tag is a fluorescent tag. In some embodiments, a tag is for detection. In some embodiments, a tag is for purification and detection. In some embodiments, a tag is a purification tag. In some embodiments, a tag is or comprises biotin. Many other types of tags are available in the art and can be utilized in accordance with the present disclosure.

[0271] Various technologies can be utilized for characterizing and / or assessing provided technologies (e.g., agents (e.g., various peptides), compositions, methods, etc.) in accordance with the present disclosure. As described herein, in some embodiments, a useful technology is or comprises fluorescence polarization. In some embodiments, a useful technology assesses LogP or LogD. In some embodiments, a useful technology is or comprises a CHI LogD assay. In some embodiments, a useful technology assesses solubility. In some embodiments, a useful technology is or comprises NanoBRET. In some embodiments, a useful technology is or comprises a reporter assay (e.g., DLD1 reporter assay). In some embodiments, a useful technology is or comprises alphascreen. Certain useful protocols are described in the Examples. Those skilled in the art appreciate that suitable adjustments may be made to such protocols, e.g., according to specific conditions, agents, purposes, etc.

[0272] In some embodiments, tumor models are utilized to assess technologies. In some embodiments, a tumor model is a patient-derived tumor model. In some embodiments, a number of tumor models are utilized. In some embodiments, a number of patient-derived tumor models are utilized. In some embodiments, tumor models carry various mutations one or more of which may be shared by two or moremodels. Certain mutations are described in the Examples. In some embodiments, tumor models can have different expression profiles. For example, tumor models carrying APC and / or beta-catenin mutations (and possible others) may have different expression profiles with respect to genes downstream of active (and hyper-active) beta-catenin / TCFs (e.g., Axin2, SP5, etc.). In some embodiments, results observed from tumor models are different from those observed in in vitro models. In some embodiments, dependence of cancer cells on the Wnt pathway / beta-catenin is not preserved in an in vitro culture. In some embodiments, Wnt pathway / beta-catenin dependence is more dramatic in organoid and in vivo contexts. In some embodiments, breadth and degree of efficacy observed in in vivo tumor models, e.g., patient-derived tumor models, are greater than that observed using in vitro models. In some embodiments, multiple tumor models, some of which are responsive to technologies herein (e.g., a stapled peptide agent) and some of which are not, are utilized to identify useful biomarkers, either individually or in combination, for selecting patients for treatment by technologies herein. In some embodiments, the present disclosure provides biomarkers, individually and in combination, to demonstrate pharmacodynamic activity in patients and / or to predict drug responses in vivo. In some embodiments, a subject is identified for treatment based on pathway mutation (e.g., APC, beta-catenin), expression of certain genes (e.g., AXIN2), beta-catenin levels and / or localization, and / or presence or absence of additional oncogenic drivers. In some embodiments, it was observed that provided technology, e.g., I-66, can provide tumor regression in multiple APC mutant CRC PDX models. Some of these responsive models contain TP53 mutation, some contain Ras mutation (K / N), some contain mutations in both, and some contain no mutations in TP53 or Ras. In some embodiments, a level of expression, transcript, polypeptide, etc., is relative to that of relevant normal cells, diseased cells (e.g., cancer cells) of one or more other subjects, etc. In some embodiments, a level of expression, transcript, polypeptide, etc., is relative to that of absence of administration of an agent and / or administration of a reference (e.g., in some embodiments, I-470 as a reference agent for I-66). Production

[0273] Various technologies are known in the art for producing provided agents. For example, various technologies for preparing small molecules, peptides (including stapled peptides) may be utilized in accordance with the present disclosure. Those skilled in the art, reading the present disclosure will well appreciate which such technologies are applicable in which aspects of the present disclosure in accordance with the present disclosure.

[0274] Stapling may be performed during and / or after peptide chain synthesis. In some embodiments, the present disclosure provides an unstapled peptide agent whose sequence is one described in Table E2 or Table E3. In some embodiments, amino acid residues are optionally protected for peptide synthesis (e.g., peptide synthesis using Fmoc-protected amino acids wherein certain side chains may be protected). In some embodiments, one or more stapling are achieved through olefin metathesis. In some embodiments, two or more stapling are formed through one olefin metathesis process. In some embodiments, the presentdisclosure provides a stapled peptide agent described in Table E2 or Table E3 or a salt thereof (e.g., a pharmaceutically acceptable salt thereof). In some embodiments, the present disclosure provides a stereoisomer of a stapled peptide agent described in Table E2 or Table E3 or a salt thereof (e.g., a pharmaceutically acceptable salt thereof). In some embodiments, the present disclosure provides a E / Z stereoisomer of a stapled peptide agent described in Table E2 or Table E3 or a salt thereof (e.g., a pharmaceutically acceptable salt thereof). In some embodiments, from the N to C direction, an olefin double bond in the first staple that comprising such a bond is Z, and an olefin double in the second staple that comprising such a bond is E (Z-E); in some embodiments, it is (Z-Z); in some embodiments, it is (E-Z); in some embodiments, it is (E-E). In some embodiments, from the N to C direction, an olefin double bond in the first (i, i+2), (i, i+3) or (i, i+4) staple that comprising such a bond is Z, and an olefin double in the first (i, i+7) staple that comprising such a bond is E (Z-E); in some embodiments, it is (Z-Z); in some embodiments, it is (E-Z); in some embodiments, it is (E-E). In some embodiments, an agent comprises an olefin double bond in a third staple, and it is E; in some embodiments, it is Z. In some embodiments, an agent comprises an olefin double bond in a fourth staple, and it is E; in some embodiments, it is Z.

[0275] In some embodiments, one or more or all staples are formed after chain extension. In some embodiments, one or more or all staples are formed during chain extension. In some embodiments, one or more or all staples by metathesis are formed after chain extension. In some embodiments, one or more or all staples by metathesis are formed during chain extension. In some embodiments, two or more staples each independently comprising an olefin are formed in one step. In some embodiments, to prepare an agent, e.g., I-66 or I-67 or an isomer thereof, metathesis is performed on an optionally protected agent (e.g., −COOH protected as esters such as t-butyl este...

Claims

CLAIMS 1. A composition, characterized in that when the composition is administered to a system expressing c- Myc, c-Myc polypeptide level is reduced, and wherein the composition comprises an agent having the structure of:,or a salt thereof.

2. The composition of claim 1, wherein reduction of c-Myc polypeptide level is observed about 7 days post a dose.

3. A composition, characterized in that when the composition is administered to a system expressing c- Myc, c-Myc polypeptide level is reduced, and wherein the composition comprises an agent having the structure of: [X]pX1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17[X]p’, wherein: each of p15, p16 and p17 is independently 0 or 1; each of p and p’ is independently 0-10; and each of X, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, and X17is independently an amino acid residue.

4. The composition of claim 3, wherein reductio of c-Myc polypeptide level is observed about 7 days post a dose.

5. The composition of any one of claims 3-4, wherein the agent is or comprises a peptide comprising: [X0]p0X1X2X3X4X5X6X7X8X9X10X11X12X13X14[X15]p15[X16]p16[X17]p17, wherein: each of p0, p15, p16 and p17 is independently 0 or 1; each of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, and X17isindependently 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.

6. The composition of any one of claims 3-5, the agent comprises three or more staples within 10-20 amino acid residues.

7. The composition of any one of claims 3-6, wherein five of X0, X1, X3, X4, X7, X10, X11and X14are each independently an amino acid residue suitable for stapling, or are each independently stapled.

8. The composition of any one of claims 3-7, wherein X1and X4are connected by a staple.

9. The composition of any one of claims 3-8, wherein X4and X11are connected by a staple.

10. The composition of any one of claims 3-9, wherein X10and X14are connected by a staple.

11. The composition of any one of the preceding claims, wherein the agent comprises three or more staples.

12. The composition of any one of the preceding claims, wherein the agent comprises a N-terminal group.

13. The composition of any one of claims 3-12, wherein X1is PL3.

14. The composition of any one of claims 3-13, wherein X4is a residue of an amino acid that comprises an olefin.

15. The composition of any one of claims 3-14, wherein X4is B5.

16. The composition of any one of claims 3-15, 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.

17. The composition of any one of claims 3-16, wherein X10is Lys.

18. The composition of any one of claims 3-17, wherein X11is a residue of an amino acid that comprises an olefin.

19. The composition of any one of claims 3-18, wherein X11is PyrS2.

20. The composition of any one of claims 3-19, 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.

21. The composition of any one of claims 3-20, wherein X14is Glu.

22. The composition of any one of claims 3-21, wherein X10and X14are connected by a staple, wherein the staple comprises −C(O)N(R’)−.

23. The composition of any one of claims 3-22, wherein X2comprises a side chain comprising an acidic group.

24. The composition of any one of claims 3-23, wherein X2is Asp, Ala, Asn, Glu, Npg, Ser, Hse, Val, S5, S6, AcLys, TfeGA, aThr, Aad, Pro, Thr, Phe, Leu, PL3, Gln, isoGlu, MeAsn, isoDAsp, RbGlu, SbGlu, AspSH, Ile, SbMeAsp, RbMeAsp, aMeDAsp, OAsp, 3COOHF, NAsp, 3Thi, NGlu, isoDGlu, BztA, Tle, Aib,MePro, Chg, Cha, or DipA.

25. The composition of any one of claims 3-24, wherein X3comprises one or two hydrophobic side chains.

26. The composition of any one of claims 3-25, wherein X3is Npg, Ile, Asp, Cha, DipA, Chg, Leu, B5, Cba, S5, Ala, Glu, AllylGly, nLeu, Ser, B6, Asn, B4, GlnR, Val, [Phc][Allyl]Dap, Hse, [Bn][Allyl]Dap, 1MeK, R5, Phe, CypA, CyLeu, Pff, DiethA, Tyr, Trp, Aib, Phg, OctG, MorphNva, F2PipNva, [Piv][Allyl]Dap, [CyCO][Allyl]Dap, Lys, or S3.

27. The composition of any one of claims 3-26, wherein X5comprises a side chain comprising an acidic group.

28. The composition of any one of claims 3-27, wherein X5is selected from Asp, 3COOHF, TfeGA, Gln, [CH2CMe2CO2H]TriAzDap, Thr, Glu, 2OH3COOHF, 4OH3COOHF, 4COOHF, 2COOHF, His, Tyr, 5F3Me2COOHF, 4F3Me2COOHF, 5F3Me3COOHF, 4F3Me3COOHF, 3F2COOHF, Val, Ser, Trp, Asn, Ala, Arg, dGlu, aThr, hTyr, 3cbmf, Leu, Phe, Lys, and Ile.

29. The composition of any one of claims 3-28, wherein X6comprises a side chain comprising an acidic group.

30. The composition of any one of claims 3-29, wherein X6is 3COOHF, TfeGA, or Asp.

31. The composition of any one of claims 3-30, wherein X7is a hydrophobic amino acid residue.

32. The composition of any one of claims 3-31, wherein X7is selected from Aib, Ala, MorphGln, Gln, Ser, iPrLys, nLeu, Cha, Hse, Npg, Val, CyLeu, Thr, Phe, Acp, Asn, DaMeS, aMeDF, Leu, Cpg, Cbg, Me2Gln, Met2O, AcLys, His, aMeL, DaMeL, aMeV, aMeS, and aMeF.

33. The composition of any one of claims 3-32, wherein X8is a hydrophobic amino acid residue.

34. The composition of any one of claims 3-33, wherein X8is selected from Ala, Aib, Cpg, Val, Leu, Gln, Lys, Asp, Glu, Aad, nLeu, Cba, Ser, Thr, aThr, MorphGln, Phe, hPhe, hTyr, and AcLys.

35. The composition of any one of claims 3-34, wherein X9comprises a side chain which is or comprises an optionally substituted aromatic group.

36. The composition of any one of claims 3-35, wherein X9is AA9, Phe, Ala, Lys, 3COOHF, Aib, 2NapA, nLeu, 2Thi, Tyr, 3Thi, 4FF, 4ClF, 4BrF, 3FF, 3ClF, 3BrF, 2FF, 3OMeF, 4CNF, 3CNF, 4MeF, 3MeF, Aic, RbiPrF, SbiPrF, RbiPrDF, RbMeXylA, RbMeXylDA, Cba, CypA, BztA, 1NapA, Trp, Leu, Ile, Ser, Chg, Hse, 4TriA, 3F3MeF, Thr, His, Val, Asn, Gln, 2Cpg, SbMeXylA, or SbMeXylDA.

37. The composition of any one of claims 3-36, wherein X12comprises a side chain which is or comprises an optionally substituted aromatic group.

38. The composition of any one of claims 3-37, wherein X12is 3Thi, Phe, 2F3MeF, PyrS2, 2ClF, hnLeu, BztA, 2Thi, 2MeF, 2FF, 34ClF, Lys, nLeu, 2COOHF, 2PhF, hCbA, hCypA, hCha, CypA, hPhe, DipA, HepG, Dap7Abu, hhLeu, hhSer, HexG, [2IAPAc]2NH2F, Ala, Abu, Leu, hLeu, Npg, Cpa, PyrS1, [Bnc]2NH2F, [Phc]2NH2F, [BiPh]2NH2F, [3PyAc]2NH2F, Nva, Cba, ChA, 2FurA, 2OMeF, 2BrF, 2CNF, 2NO2F, 2PyrA, 3PyrA, 4PyrA, His, 1NapA, Val, Ile, Chg, DiethA, OctG, 2cbmF, c6Phe, [MePipAc]2NH2F,or [2PyCypCO]2NH2F.

39. The composition of any one of claims 3-38, wherein the side chain of X13comprises an optionally substituted aromatic group.

40. The composition of any one of claims 3-39, wherein X13is selected from BztA, 34ClF, 2NapA, 3BrF, 34MeF, 3Thi, Phe, GlnR, 34MeF, 2NapA and Lys.

41. The composition of any one of claims 3-40, wherein p15 is 1.

42. The composition of any one of claims 3-41, wherein X15comprises a hydrophobic side chain.

43. The composition of any one of claims 3-42, wherein the peptide forms a structure that comprises a helix.

44. The composition of any one of claims 3-43, wherein a double bond of a (i, i+7) staple is E.

45. The composition of any one of claims 3-44, wherein a double bond of a (i, i+7) staple is Z.

46. The composition of any one of claims 3-45, wherein a double bond of a (i, i+2), (i, i+3) or (i, i+4) staple is E.

47. The composition of any one of claims 3-46, wherein a double bond of a (i, i+2), (i, i+3) or (i, i+4) staple is Z.

48. The composition of any one of claims 3-47, wherein a carbon atom bonded to two staples (e.g., in B5) is of R configuration.

49. The composition of any one of claims 3-47, wherein a carbon atom bonded to two staples (e.g., in B5) is of S configuration.

50. The composition of claim 1, wherein the agent has the structure of 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.

51. The composition of claim 1, wherein the agent has the structure ofor a salt thereof.

52. The composition of claim 51, wherein the agent has the same retention time under a HPLC condition as I-66 prepared as described in Example 3, wherein the HPLC condition can separate I-66 and I-67 prepared as described in Example 3.

53. The composition of claim 51, wherein the agent shows a retention time of about 15.3 min under the following HPLC condition: Agilent Poroshell 120 EC-C18; 4.6 x 100 mm; solvent A = 0.1% TFA in water; solvent B = 0.075% TFA in acetonitrile; gradient is 10% B to 95% B over 30 min; detection is UV absorbance at 220 nM.

54. The composition of claim 48, wherein chemical shifts of1H bonded to carbon of the agent are (methanol-d4, about 298K, about 900 MHz): 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.50, 4.40, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7.00, 4.30, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.20, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, and 2.

23.

55. The composition of claim 48, wherein chemical shifts of13C of the agent are (methanol-d4, about 298K, about 226 MHz, chemical shift): 65.89, 137.36, 138.13, 57.28, 138.06, 132.12, 169.51, 62.78, 31.36, 70.51, 132.57, 139.58, 141.98, 156.51, 173.13, 175.55, 175.8, 174.47, 175.8, 177.56, 178.58, 174.39, 175.7, 177.0, 175.8, 175.44, 175.6, 176.97, 175.55, 178.08, 172.38, 59.94, 123.42, 125.19, 129.15, 56.93, 55.69, 57.70, 60.70, 130.39, 129.83, 128.08, 129.83, 130.39, 54.54, 60.94, 131.96, 129.37, 129.54, 135.08, 55.56, 131.26, 131.47, 56.48, 55.33, 129.2, 126.96, 122.71, 125.37, 125.20, 123.87, 126.99, 51.20, 29.99, 30.63,67.18, 53.94, 31.81, 45.37, 32.60, 27.47, 33.84, 39.25, 23.2, 35.8, 29.61, 38.18, 38.10, 36.18, 30.00, 23.32, 33.8, 45.96, 35.69, 33.09, 27.46, 23.29, 35.96, 49.50, 24.46, 36.46, 31.76, 17.00, 30.18, 17.76, 28.98, 23.20, 23.87, 172.48, and 174.

10.

56. A composition, characterized in that when the composition is administered to a system expressing c- Myc, c-Myc polypeptide level is reduced, and wherein the composition comprises: an agent having the structure of: 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 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; 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, bicyclicor 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; or an agent having 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, 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-C6aliphatic 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 a covalent bond or 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 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 withtheir 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.

57. The composition of any one of the preceding claims, wherein the agent has a diastereopurity of about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more, or having a purity of about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more.

58. The compositions of any one of the preceding claims, wherein N-Myc transcript level is reduced.

59. The compositions of any one of the preceding claims, wherein N-Myc polypeptide level is reduced.

60. The compositions of any one of the preceding claims, wherein C-Myc transcript level is reduced.

61. The compositions of any one of the preceding claims, wherein levels of FGF20, NOTUM, Axin2, and / or DKK4 transcripts are independently reduced.

62. The compositions of any one of the preceding claims, wherein levels of FGF20, NOTUM, Axin2, and / or DKK4 polypeptides are independently reduced.

63. The compositions of any one of the preceding claims, wherein the system expresses beta-catenin.

64. The compositions of any one of the preceding claims, wherein the system is or comprises colorectal cancer cells.

65. The compositions of any one of the preceding claims, wherein the system is or comprises COLO320DM cells in a mouse xenograft model.

66. The compositions of any one of the preceding claims, wherein the system is or comprises colorectal cancer cells in a patient-derived colorectal cancer mouse xenograft model.

67. The compositions of any one of the preceding claims, wherein the system is or comprises cancer cells in a subject.

68. The compositions of any one of the preceding claims, wherein the system is or comprises an APC mutation.

69. The compositions of any one of the preceding claims, wherein the reduction of c-Myc polypeptide is about or at least about 50%, 60%, 70%, 80% or 90% compared to absence of the agent.

70. The compositions of any one of the preceding claims, wherein the reduction of c-Myc polypeptide can be observed about 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 days after a dose.

71. The compositions of any one of the preceding claims, wherein the reduction of c-Myc polypeptide can be observed about 2 days after the second dose.

72. The compositions of any one of the preceding claims, wherein the reduction of c-Myc polypeptide can be observed about 7 days after the second dose.

73. The composition of any one of claims 71-72, wherein the two doses are administered every 4 days.

74. The compositions of any one of the preceding claims, wherein the system is a mouse PDX model, one or each dose administered to a mouse is independently about 20-80 mg / kg, and c-Myc polypeptide level in the tumor is reduced.

75. A pharmaceutical composition, comprising or delivering an agent described in any one of thepreceding claims, and a pharmaceutically acceptable carrier.

76. A composition selected from Table E2 or Table E3, or a pharmaceutical composition, comprising or delivering one or more or all peptide agents in a composition selected from Table E2 or Table E3, and a pharmaceutically acceptable carrier.

77. The composition of any one of the preceding claims, comprising an agent comprising one or more staples each independently comprises one or more olefin double bond, wherein the ratio of the two stereoisomers of an olefin double bond in a staple is about 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1, 20:1, 30:1, 40:1, 50:1 or more.

78. A method, comprising a) preparing a first compound comprising two moieties each of which independently comprises an olefin double bond; b) providing a second compound by stapling the two moieties by olefin metathesis of an olefin double bond of one moiety with an olefin double bond of the other to form a first-formed staple; c) add one or more additional moieties to the second compound to provide a third compound which comprising two moieties each of which independently comprises an olefin double bond; and d) providing a fourth compound by stapling the two moieties in the third compound by olefin metathesis of an olefin double bond of one moiety with an olefin double bond of the other to form a second- formed staple; or a method, comprising: contacting an agent comprising -PL3-Asp(PG)-Npg-B5-Asp(PG)-3COOHF(PG)-Aib-Ala-Phe- Lys*3-PyrS2-3Thi-BztA-GlnR*3-Ala- or a salt form thereof, wherein each PG is independently protecting group for −COOH, with an agent that can promote olefin metathesis to provide an agent comprising -PL3- Asp(PG)-Npg-B5-Asp(PG)-3COOHF(PG)-Aib-Ala-Phe-Lys*3-PyrS2-3Thi-BztA-GlnR*3-Ala- wherein PL3 and B5, and B5 and PyrS2 are independently stapled; or contacting an agent comprising -B5-Asp(PG)-3COOHF(PG)-Aib-Ala-Phe-Lys*3-PyrS2- or a salt form thereof, wherein each PG is independently protecting group for −COOH, with an agent that can promote olefin metathesis to provide an agent comprising -B5-Asp(PG)-3COOHF(PG)-Aib-Ala-Phe-Lys*3-PyrS2- wherein B5 and PyrS2 is stapled; or contacting an agent comprising -PL3-Asp(PG)-Npg-B5-Asp(PG)-3COOHF(PG)-Aib-Ala-Phe- Lys*3-PyrS2- or a salt form thereof, wherein there is a staple between B5 and PyrS2, and wherein each PG is independently a protecting group, with an agent that can promote olefin metathesis to provide an agent comprising -PL3-Asp(PG)-Npg-B5-Asp(PG)-3COOHF(PG)-Aib-Ala-Phe-Lys*3-PyrS2- or a salt form thereof, wherein B5 and PyrS2, and B5 and PL3, are independently stapled; or a method, comprising: providing an agent comprising -Lys-PyrS2-3Thi-BztA-Glu- or a salt thereof; and reacting −NH2of Lys and −COOH of Glu to provide an agent comprising -Lys*3-PyrS2-3Thi-BztA-GlnR*3-.

79. A method for reducing Myc transcript and / or polypeptide levels in a system, comprising contacting beta-catenin with an agent described in or a composition of any one of the preceding claims; or a method for reducing Axin2 transcript and / or polypeptide levels in a system, comprising contacting beta-catenin with an agent described in or a composition of any one of the preceding claims; a method for reducing DKK4 transcript and / or polypeptide levels in a system, comprising contacting beta-catenin with an agent described in or a composition of any one of the preceding claims; a method for reducing NOTUM transcript and / or polypeptide levels in a system, comprising contacting beta-catenin with an agent described in or a composition of any one of the preceding claims; a method for reducing FGF20 transcript and / or polypeptide levels in a system, comprising contacting beta-catenin with an agent described in or a composition of any one of the preceding claims; a method for modulating beta-catenin interaction with a partner in a system, comprising contacting beta-catenin with an agent described in or a 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 described in or a composition of any one of the preceding claims; or a method for modulating a TCF-beta-catenin interaction in a system, comprising contacting beta- catenin with an agent described in or a 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 described in or a composition of any one of the preceding claims; or a method for inhibiting beta-catenin dependent cell proliferation, comprising administering or delivering to the system an agent described in or a 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 described in or a composition of any one of the preceding claims, wherein expression of a nucleic acid is modulated; or a method, comprising administering or delivering to the system an agent described in or a composition of any one of the preceding claims, wherein level of a transcript of a nucleic acid and / or a product thereof is modulated; or a method, comprising administering or delivering to the system an agent described in or a composition of any one of the preceding claims, wherein expression of a nucleic acid is modulated.

80. A method for treating or preventing a condition, disorder or disease associated with beta-catenin interaction with a partner in a subject, comprising administering or delivering to the subject an effective amount of an agent described in or a composition of any one of the preceding claims, preferably wherein the partner is TCF7, LEF1, TCF7L1, TCF7L2, Axin1, Axin2, or APC.

81. A method for treating cancer in a subject, comprising administering or delivering to the subject an effective amount of an agent described in or a composition of any one of the preceding claims.

82. The method of claim 81, wherein cancer cells of the subject express high levels of Myc.

83. The method of any one of claims 81-82, wherein cancer cells of the subject has APC mutation.

84. The method of any one of claims 81-83, wherein cancer cells of the subject has Ras mutation.

85. The method of any one of claims 81-84, wherein cancer cells of the subject has TP53 mutation.

86. The method of any one of claims 81-85, wherein the cancer is colorectal cancer.

87. The method of any one of claims 81-86, comprising administering or deliver to a subject a second therapeutic agent or therapy.

88. The method of any one of claims 81-87, wherein a second therapeutic agent is or comprises a chemotherapy agent, a hormone therapy agent, an immunotherapy agent, a checkpoint inhibitor, an antibody, a CTLA-4, PD-1 or PD-L1 inhibitor, or a cell, or a second therapy is or comprises surgery, chemotherapy, radiotherapy, hormone therapy, stem cell or bone marrow transplant, immunotherapy, T-cell therapy, or CAR T-cell therapy.

89. The method of any one of claims 81-88, comprising assessing expression of a nucleic acid.

90. An agent, compound, method, or composition of any one of Embodiments 1-818.

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