Compositions and methods for treating autoimmune diseases

Abstract

Provided herein are compositions and methods for treating an autoimmune disease or disorder in a subject. In some cases, the compositions and methods use chemical inducers of proximity (CIPs). In some cases, the CIPs include a first moiety having specific binding for a BTB domain-containing protein or a transcriptional repressor expressed in B cell subpopulations and a second moiety having specific binding for a modulator of gene regulation. In some cases, the BTB domain-containing protein comprises BCL6. In some cases, the transcriptional repressor expressed in B cell subpopulations is PRDM1 or IRF4. In some cases the modulator of gene regulation comprises BRD4, CDK9, and / or p300.

Description

WSGR Docket No. 65514-707.601COMPOSITIONS AND METHODS FOR TREATING AUTOIMMUNE DISEASESCROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Patent Application Number 63 / 740,623 filed on December 31, 2024, which is incorporated by reference herein in its entirety.BACKGROUND

[0002] Methods of controlled regulation of gene expression have been increasingly important in a wide range of areas, including, but not limited to, gene therapy, synthetic biology, plant management, environmental clean-up, bacterial and microbial management and synthetic genetic circuits. Control of gene expression holds vast potential at revolutionizing therapeutics, animal models, and biotechnological processes and is useful to integrate multiple input signals for cell -based therapy and animal model development. Despite rapid advances in recent years, precise control of gene expression remains a challenge due to unpredictability stemming from unintended interactions between biological components, such as transcription factors, etc. A fundamental goal in cellular engineering is to predictably and efficiently express genes at a desired level and under precise control. Such genetically engineered cells hold great promise for advancing therapeutics, diagnostics, animal models, and biotechnological processes.

[0003] To date, a variety of different gene modulation technologies for modulating gene expression in a cell have been developed. Such gene modulation technologies include RNA interference, DNA editing and expression, and chemical compounds that suppress, enhance, or modify gene expression. These can be in the form of RNA, DNA, or protein, and can be introduced into cells in culture through direct application to media, lipofection, electroporation, or viral transduction.

[0004] However, because of the wide applicability of gene modulation to both research and therapeutic applications, there is a continued interest in the development of new ways to modulate transcription of a target gene in a cell, specifically to modulate expression of genes without genetic modification.SUMMARY

[0005] In one aspect, provided herein is a method of treating an autoimmune disease or disorder in a subject, the method comprising administering to the subject a chemical inducer of proximity (CIP) which couples a BTB domain-containing protein or a transcriptional repressor expressed in B cell subpopulations with a modulator of gene regulation, in an amount effective to treat the autoimmune disease or disorder. In some cases, the autoimmune disease or disorder is associated with presence of active, hyperactive, or ectopic germinal centers. In some cases, the autoimmune disease or disorder is selected from the group consisting of: rheumatoid arthritis (RA), Sjogren’s syndrome (SS), immunoglobulin G4-related disease (IgG4-RD), juvenile arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, autoimmune thyroid disease (i.e. Graves Disease), multiple sclerosis, autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), Evan’s syndrome, systemic lupus erythematosus (SLE), dermatomyositis, scleroderma, organ rejection, Crohn’s disease, myastheniaWSGR Docket No. 65514-707.601gravis, diabetes type 1, diabetes type 2, Reiter’s syndrome, Neuromyelitis optica spectrum disorder (NMOSD), Pemphigus vulgaris, Anti-GBM (Goodpasture) disease, acquired hemophilia A, immune-mediated (acquired) TTP, seronegative enthesopathy and arthropathy (SEA) syndrome, prothrombotic autoantibody syndromes such as antiphospholipid syndrome (APS), psoriasis, and atopic dermatitis

[0006] In some cases, after the administering, levels of B cells are reduced. In some cases, the administering is selected from the group consisting of: oral administration, intravenous administration, intramuscular administration, intraarticular administration, subcutaneous administration, topical administration, and intralesional administration.

[0007] In another aspect, provided herein is a method of reducing a level of B cells, the method comprising contacting a B cell with a chemical inducer of proximity (CIP) which couples a BTB domain containing protein or a transcriptional repressor expressed in B cell subpopulations with a modulator of gene regulation, such that the B cell undergoes apoptosis, thereby reducing the level of B cells.

[0008] In some cases, the BTB domain-containing protein is or comprises BCL6. In some cases, the BTB domain-containing protein is or comprises a protein selected from Table 1. In some cases, the transcriptional repressor expressed in B cell subpopulations is PRDM1. In some cases, the transcriptional repressor expressed in B cell subpopulations is IRF4. In some cases, the modulator of gene regulation is or comprises BRD4. In some cases, the modulator of gene regulation is or comprises CDK9. In some cases, the modulator of gene regulation is or comprises p300. In some cases, the modulator of gene regulation is or comprises a protein selected from Table 2. In some cases, the CIP has the structure of Formula I or Formula II:A-linker-B(Formula I); orA-B(Formula II),wherein A is a first moiety that specifically binds to the BTB domain-containing protein or the transcriptional repressor expressed in B cell subpopulations, and wherein B is a second moiety that specifically binds to the modulator of gene regulation. In some cases, the linker is a chemical linker. In some cases, the linker has a molecular weight of less than about 2,000 g / mol. In some cases, the linker has a molecular weight of about 50 g / moL to about 2000 g / moL. In some cases, the linker has a LogP of less than about 10. In some cases, the linker has less than about 50 rotatable bonds. In some cases, the linker has a Topological Polar Surface Area (TPSA) of less than about 300. In some cases, the linker is asymmetrical, symmetrical, or a bond.

[0009] In some cases, A is a small molecule compound. In some cases, B is a small molecule compound. In some cases, the CIP induces expression of at least one proapoptotic gene in a cell. In some cases, the at least one proapoptotic gene is selected from the group consisting of: TP 53, PUMA (BBC3), BIM(BCL2L11), BID, BAX, BAK, BOK, BAD, HRK, BIK, BMF, and NOXA. In some cases, the BTB domain-containing protein or the transcriptional repressor expressed in B cell subpopulations and the modulator of gene regulation are both endogenous proteins. In some cases, the BTB domain-WSGR Docket No. 65514-707.601containing protein or the transcriptional repressor expressed in B cell subpopulations and the modulator of gene regulation are both expressed in the same cell.INCORPORATION BY REFERENCE

[0010] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0012] FIG. 1 illustrates the expression of zinc finger and BTB domain- containing (ZBTB) proteins during B-cell development.

[0013] FIG. 2 provides the structure of the CIP JWZ-7-7.

[0014] FIG.3 illustrates the effect of rewiring BCL6 from a repressor into an activator on the viability of BCL6-high B cells.

[0015] FIG.4 demonstrates the effect of a BCL6-BRD4 CIP on cell viability of SUDHL5 cells, which is a BCL6-high germinal center (GC) DLBCL cell line, (n = 3 replicates, mean + / - s.d.)

[0016] FIG. 5 demonstrates that in BCL6-high germinal center (GC) DLBCL cells, treatment with a BCL6-BRD4 CIP induces a pronounced transcriptional switch.

[0017] FIG.6 shows a coordinated shutdown of hallmark GC identity genes in BCL6-high GC-DLBCL (SUDHL5) cells treated with a BCL6-BRD4 CIP, consistent with collapse of the GC transcriptional program.

[0018] FIG. 7 demonstrates the effect of a BCL6-BRD4 CIP on cell viability of CD14+, FACS sorted human monocytes and CD19+, FACS sorted human peripheral B cells. Human peripheral B cells are naive or memory B cells, which are BCL6 negative / low. (n = 3 replicates, mean + / - s.d.)DETAILED DESCRIPTION

[0019] Provided herein are chemical inducers of proximity (CIPs) which couple a BTB domaincontaining protein or a transcriptional repressor expressed in B cell subpopulations with a modulator of gene regulation. In some cases, the modulator of gene regulation is a transcriptional modulator. In some cases, the modulator of gene regulation is an epigenetic modulator. In some cases, the modulator of gene expression is a chromatin-modifying protein. In some cases, the BTB domain- containing protein is or comprises BCL6. In some cases, the BTB domain-containing protein is or comprises a protein selected from Table 1. In some cases, the transcriptional repressor expressed in B cell subpopulations is PRDM1. In some cases, the transcriptional repressor expressed in B cell subpopulations is IRF4. In some cases, the modulator of gene regulation is or comprises, without limitation, BRD4, p300, CBP, BRD2, BRD3,WSGR Docket No. 65514-707.601BRDT, MLL1-4, ENL, CDKs (e.g. CDK9), LSD1, components of the mammalian BAF -complex (e.g., SMARCA2, SMARCA4), KDM6A, KDM6B, KDM7A, BRD9, demethylases (e.g., TET1-3). In some cases, the modulator of gene regulation is or comprises a protein selected from Table 2. Further provided herein are methods of using the CIPs to treat autoimmune diseases or disorders in a subject. The CIPs provided herein can be used to bring different endogenous proteins (e.g., a BTB domaincontaining protein (e.g., BCL6) or a transcriptional repressor expressed in B cell subpopulations (e.g., PRDM1, IRF4) and a modulator of gene regulation (e.g., BRD4, CDK9, P300) expressed by the target cell into spatial proximity such that a target gene (e.g., a proapoptotic gene) is regulatable by the modulator of gene regulation that, in the absence of the CIP, would not ordinarily be regulatable by said modulator of gene regulation. For example, the CIPs provided herein can be used to regulate expression of a target gene (e.g., a proapoptotic gene) by bringing a modulator of gene regulation into close spatial proximity with the target gene. The CIPs provided herein can be used to target a cell that expresses a BTB domain-containing protein (e.g., BCL6) or a transcriptional repressor expressed in B cell subpopulations (e.g., PRDM1, IRF4), and expresses the modulator of gene regulation. In some cases, the cell is aB cell. In some cases, the cell is aB cell of a germinal center. In some cases, the cell is a B cell of an active, a hyperactive, or ectopic germinal center. In some cases, the cell is a plasma cell. The CIP, when introduced into a cell, brings the modulator of gene regulation into close spatial proximity such that the modulator of gene regulation turns on expression of a target gene (e.g., a proapoptotic gene).

[0020] Advantageously, the compositions and methods provided herein do not require any genetic modification to the target cell. Instead, the compositions and methods provided herein rely on the presence of proteins endogenously expressed in the target cell (e.g., BCL6, BRD4, CDK9, p300). In addition, the CIP is generally a small molecule that can be administered to a subject (e.g., by oral administration, by intravenous administration, etc.).

[0021] As used herein, the term “about” a number refers to that number plus or minus 10% of that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.

[0022] In one aspect, provided herein are methods for treating autoimmune diseases or disorders in a subject. In some cases, the autoimmune disease or disorder is associated with the presence of active, hyperactive, or ectopic germinal centers. In some cases, the autoimmune disease or disorder is selected from the group consisting of: rheumatoid arthritis (RA), Sjogren’s syndrome (SS), immunoglobulin G4-related disease (IgG4-RD), juvenile arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, autoimmune thyroid disease (i.e. Graves Disease), multiple sclerosis, autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), Evan’s syndrome, systemic lupus erythematosus (SLE), dermatomyositis, scleroderma, organ rejection, Crohn’s disease, myasthenia gravis, diabetes type 1, diabetes type 2, Reiter’s syndrome, Neuromyelitis optica spectrum disorder (NMOSD), Pemphigus vulgaris, Anti-GBM (Goodpasture) disease, acquired hemophilia A, immune-mediated (acquired) TTP, seronegative enthesopathy and arthropathy (SEA) syndrome, prothrombotic autoantibody syndromes such as antiphospholipid syndrome (APS), psoriasis, and atopic dermatitis. In some cases, the active,WSGR Docket No. 65514-707.601hyperactive, or ectopic germinal centers express a BTB domain-containing protein (e.g., BCL6). In some cases, the active, hyperactive, or ectopic germinal centers express a transcriptional repressor expressed in B cell subpopulations (e.g., PRDM1, IRF4). In some cases, the active, hyperactive, or ectopic germinal centers express the modulator of gene regulation (e.g., BRD4, CDK9, and / or p300). In exemplary cases, the active, hyperactive, or ectopic germinal center (or a cell therein) expresses both the BTB domaincontaining protein or the transcriptional repressor expressed in B cell subpopulations, and the modulator of gene regulation. In some cases, the BTB domain- containing protein or the transcriptional repressor expressed in B cell subpopulations and the modulator of gene regulation are both expressed in a cell, such as aB cell. The B cell can be associated with a germinal center. The B cell can be associated with an active, a hyperactive, or an ectopic germinal center. The B cell can be a plasma cell (plasma B cell).

[0023] In another aspect, provided herein are methods for reducing levels of B cells. In some cases, the methods involve contacting the B cell with a CIP which couples a BTB domain- containing protein (e.g., BCL6) or a transcriptional repressor expressed in B cell subpopulations (e.g., PRDM1, IRF4) with at least one modulator of gene regulation (e.g., BRD4, CDK9, p300). In some cases, the B cell (or ectopic germinal center B cells) expresses the BTB domain- containing protein (e.g., BCL6). In some cases, the B cell (or ectopic germinal center B cells) expresses the transcriptional repressor expressed in B cell subpopulations (e.g., PRDM1, IRF4). In some cases, the B cell expresses the modulator of gene regulation (e.g., BRD4, CDK9, and / or p300). In some cases, the B cell is associated with a germinal center. In some cases, the B cell is associated with an ectopic germinal center. In some cases, the B cell is a plasma cell (plasma B cell).

[0024] As described herein, the compositions and methods provided herein involve the use of CIPs that have at least a first moiety and a second moiety, where the first moiety specifically binds to the BTB domain-containing protein or the transcriptional repressor expressed in B cell subpopulations, and the second moiety specifically binds to a modulator of gene regulation. In some cases, the BTB domaincontaining protein is or comprises a protein selected from Table 1. In some cases, the BTB domaincontaining protein is or comprises BCL6. In some cases, the modulator of gene regulation is or comprises a protein selected from Table 2. In some cases, the modulator of gene regulation is or comprises BRD4, CDK9, and / or p300. A moiety of the CIP may be referred to as a ligand throughout the present disclosure, and the terms “moiety” and “ligand” (or “moieties” and “ligands”) may be used interchangeably herein. The BTB domain- containing protein or the transcriptional repressor expressed in B cell subpopulations and the modulator of gene regulation each originated from and are expressed in the cell. In particular, the BTB domain- containing protein or the transcriptional repressor expressed in B cell subpopulations and the modulator of gene regulation are both present or expressed in the cell at the time in which the CIP disclosed herein is administered. The compositions and methods provided herein generally do not require concurrent exogenous introduction (such as transfecting, transducing, and the like) of the BTB domain- containing protein or the transcriptional repressor expressed in B cell subpopulations or the modulator of gene regulation into the cell to which a subject compound is administered in order to achieve the gain of function. The compositions and methods provide specificityWSGR Docket No. 65514-707.601such that the gain of function is only achieved in a specific target cell where both the BTB domaincontaining protein or the transcriptional repressor expressed in B cell subpopulations and the modulator of gene regulation are expressed. In some embodiments, the CIPs of the disclosure comprise at least a first moiety that binds to the BTB domain- containing protein or the transcriptional repressor expressed in B cell subpopulations and a second moiety that binds to the modulator of gene regulation, thereby forming a ternary complex between the BTB domain-containing protein or the transcriptional repressor expressed in B cell subpopulations and the modulator of gene regulation. Upon administration of the CIP, the BTB domain- containing protein or the transcriptional repressor expressed in B cell subpopulations and the modulator of gene regulation are associated in spatial proximity to one another.

[0025] The ternary complex (e.g., between the BTB domain-containing protein or the transcriptional repressor expressed in B cell subpopulations, and the modulator of gene regulation) is a non-naturally occurring complex that would otherwise not exist in the cell in the absence of the CIP and both the BTB domain-containing protein or the transcriptional repressor expressed in B cell subpopulations and the modulator of gene regulation. The first and second moieties of the CIP can be derived from naturally occurring and / or synthetic substances. Applicable and readily observable or measurable criteria for selecting the moieties can include, but are not limited to: (A) the moiety is physiologically acceptable (e.g., lacks undue toxicity towards the cell or animal for which it is to be used); (B) the moiety has a reasonable therapeutic dosage range (e.g., as ascertained by yielding a desired expression profde of a target gene, or a desired cellular activity in the cell); (C) the moiety can cross the cellular and other membranes, as necessary; and / or (D) the moiety binds to one or more target domains of the BTB domaincontaining protein or the transcriptional repressor expressed in B cell subpopulations and / or the modulator of gene regulation. For example, a desirable criterion is that the CIP is chemically stable and capable to form the complex. In some instances, a moiety (e.g., the first and / or second moiety) of the CIP can be non-peptide and non-nucleic acid. Alternatively or additionally, at least a portion of the first and / or second moiety of the CIP can be a peptide and / or a nucleic acid.

[0026] A composition comprising at least the CIP (e.g., a pharmaceutical composition) can be administered to a subject, e.g., to treat an autoimmune disease or disorder of the subject. A mode of the administration can be, for example, intraarticular, oral, parenteral, intravenous, intramuscular, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intravesicular, intraurethral, intrathecal, epidural, aural, intralesional, and / or ocular administration. For example, the composition can be taken orally (e.g., compounds that are stable in the gastrointestinal system and can be absorbed into the vascular system).

[0027] The CIPs can be small molecules. The CIPs can be non-toxic. The term small molecule as used herein means a molecule having a molecular weight of 5000 g / mole (Dalton) or less, such as 2500 g / mole (Dalton) or less, including 1000 g / mole (Dalton) or less, e.g., 500 g / mole (Dalton) or less. In some instances, the CIP employed in embodiments of the disclosure has a molecular weight ranging from 250 to 1500 g / mole, such as 300 to 1200 g / mole.WSGR Docket No. 65514-707.601

[0028] The CIPs can comprise a plurality of moieties (such as a first and second moiety) to bind to a plurality of endogenous proteins, respectively. Within a single CIP, the first and second moieties can be coupled or linked to one another via a linker (e.g., a linker having at least one atom). The linker can be present to provide a distance (e.g., a desired distance) between the two moieties. Alternatively, the two moieties can be directly coupled to one another in absence of a linker (e.g., the two moieties can be coupled to one another via a direct chemical bond between two atoms of the two moieties). For example, the CIP can comprise two moieties with a chemical bond directly between the two moieties, such that the two moieties of the CIP form two sides (or two surfaces) of the CIP that each bind to its respective protein.

[0029] The CIP can comprise a plurality of moieties, each moiety binding to a different endogenous protein. For example, the CIP can comprise at least or up to about 2 moieties, at least or up to about 3 moieties, at least or up to about 4 moieties, at least or up to about 5 moieties, at least or up to about 6 moieties, at least or up to about 7 moieties, at least or up to about 8 moieties, at least or up to about 9 moieties, or at least or up to about 10 moieties. The CIP can bind to and form a complex with at least or up to 2 endogenous proteins, at least or up to 3 endogenous proteins, at least or up to 4 endogenous proteins, at least or up to 5 endogenous proteins, at least or up to 6 endogenous proteins, at least or up to 7 endogenous proteins, at least or up to 8 endogenous proteins, at least or up to 9 endogenous proteins, or at least or up to 10 endogenous proteins.

[0030] In some cases, the BTB domain- containing protein (e.g., BCL6) binds to a target gene, such as a proapoptotic gene, or to a region near a target gene, such as a promoter or a regulatory region. BCL6 may bind to the target gene, or a region near the target gene, in the absence of the CIP. In some cases, the binding of the BTB domain- containing protein (e.g., BCL6) to the target gene (or region near the target gene) may be direct binding. In other cases, the binding of the BTB domain-containing protein (e.g., BCL6) to the target gene (or region near the target gene) may be indirect binding, such as by binding to one or more co-factors, which co-factor(s) binds directly to the target gene. The BTB domaincontaining protein (e.g., BCL6) may bind to a moiety of the CIP and form a ternary complex with the CIP and the modulator of gene regulation. In such scenarios, the BTB domain-containing protein (in the ternary complex) may bind to the target gene, or a region near the target gene, and bring the modulator of gene regulation into close proximity to the target gene, or the region near the target gene. In some embodiment, the BTB domain- containing protein may act as an “anchor protein” because the BTB domain-containing protein anchors the ternary complex to the target gene. In some cases, the BTB domain-containing protein may regulate expression of the target gene in the absence of the CIP. For example, the BTB domain-containing protein may reduce or inhibit expression of the target gene, in the absence of the CIP.

[0031] In some cases, the modulator of gene regulation, in the absence of the CIP or formation of a ternary complex with the CIP, substantially lacks any effect on expression of the target gene, but in the presence of the CIP (e.g., when it forms a ternary complex with the CIP and the BTB domain- containing protein ) is recruited to the target gene and is capable of regulating expression of the target gene.WSGR Docket No. 65514-707.601

[0032] In some cases, the CIP can comprise a first moiety (e.g., covalently) linked to a second moiety, wherein: (i) the first moiety exhibits specific binding to a BTB domain-containing protein (e.g., BCL6) that binds the target gene or a region near the target gene (e. g., a promoter, a regulatory region, etc. ) or a transcriptional repressor expressed in B cell subpopulations (e.g., PRDM1, IRF4); and (ii) the second moiety exhibits specific binding to a modulator of gene regulation (e.g., BRD4, CDK9, p300).

[0033] In various aspects, a CIP is provided of Formula (I) or Formula (II):A-linker-B (Formula I); orA-B (Formula II)wherein: (a) A is or comprises a first moiety that specifically binds to BTB domain- containing protein or the transcriptional repressor expressed in B cell subpopulations; and (b) B is or comprises a second moiety that specifically binds to a modulator of gene regulation. In some cases, A is or comprises a first moiety that specifically binds to BCL6. In some cases, B is or comprises a second moiety that specifically binds to BRD4, CDK9, and / or p300. In some cases, the BTB domain- containing protein binds to a target gene or a region near a target gene (e.g., a promoter, a regulatory region). In some cases, the compound spatially complexes the BTB domain- containing protein or the transcriptional repressor expressed in B cell subpopulations with the modulator of gene regulation. In some cases, spatially complexing the BTB domain-containing protein or the transcriptional repressor expressed in B cell subpopulations with the modulator of gene regulation yields a gain-of-function in the cell, wherein the gain-of-function is characterized by modulating expression of the target gene in a manner dependent on the presence of the modulator of gene regulation bound to the CIP. In some cases, the gain-of-function is achieved by utilizing less than about 50% of an amount of the modulator of gene regulation present in the cell. In some cases, the CIP mediates the gain-of-function with an EC50 of less than about 1 micromolar. In some cases, the BTB domain-containing protein or the transcriptional repressor expressed in B cell subpopulations reduces the expression of the target gene in the absence of the CIP and the modulator of gene regulation enhances expression of an additional target gene in the absence of the CIP, wherein the gain-of-function is characterized in that expression of the target gene is enhanced as compared to that in the absence of the CIP, and expression of the additional target gene is reduced as compared to that in the absence of the CIP. In some cases, expression of the target gene is regulated in less than or equal to about 16 hours.

[0034] In some cases, the CIPs provided herein comprise a first moiety that specifically binds to a BTB domain containing proteins. The BTB domain- containing protein comprises or is any protein selected from Table 1. In some cases, the BTB domain-containing protein comprises or is BCL6. The terms “BTB domain,” (also termed a “BR-C, ttk and bab domain,” a “POZ domain,” or a “Pox virus and Zinc finger domain,”) generally refer to a domain (e.g., a structural domain) of a protein that mediates multimerization of proteins (e.g., homomeric dimerization, heteromeric dimerization, etc.). Specific examples of such proteins are provided in greater detail below (e.g., see example proteins comprising a BTB domain in Table 3). FIG. 1 depicts a schematic representation illustrating the role of zinc finger and BTB domain-containing (ZBTB) proteins in regulating the development, differentiation, and function ofWSGR Docket No. 65514-707.601B lymphocytes, any of which are suitable for targeting via the CIPs provided herein. BTB domaincontaining proteins, such as BCL6 homologues, shown in Table 1, include family members which are known to repress cell death genes including p53, Puma, Bim and others. Repression of cell death genes is due to the binding of epigenetic repressors such as BCOR, SMRT, NCOR and others. The BTB domain of this family is critical for this repression and point mutations in the BTB domain near the corepressor binding sites release repression and result in abnormal cell death. Because the BTB family has functional similarities to BCL6, ligands for their BTB domains are useful for building CIPs similar to the ones described herein for BCL6. FIG. 3 depicts a schematic of a CIP that converts BCL6 from a transcriptional repressor into an activator by recruiting a transcriptional activating factor (TFA) to its BTB domain.Table 1. BTB domain- containing proteinsABTB1 HIC2 KLHL23 RCBTB1 ZBTB37 ABTB2 IBTK KLHL24 RCBTB2 ZBTB38 ANKFY1 IPP KLHL25 RHOBTB1 ZBTB39 BACH1 IVNS1ABP KLHL26 RHOBTB2 ZBTB4 BACH1 KBTBD11 KLHL28 RHOBTB3 ZBTB40 BACH 2 KBTBD12 KLHL29 SLX4 ZBTB41BCL6 KBTBD13 KLHL3 SPOP ZBTB42 BCL6B KBTBD2 KLHL30 SPOPL ZBTB43 BTBD1 KBTBD3 KLHL31 ZBTB1 ZBTB44 BTBD11 KBTBD4 KLHL32 ZBTB10 ZBTB45 BTBD17 KBTBD6 KLHL33 ZBTB11 ZBTB46 BTBD18 KBTBD7 KLHL35 ZBTB12 ZBTB47 BTBD19 KBTBD8 KLHL36 ZBTB14 ZBTB48 BTBD2 KEAP1 KLHL38 ZBTB16 ZBTB49 BTBD3 KLHL1 KLHL4 ZBTB17 ZBTB5 BTBD6 KLHL10 KLHL40 ZBTB18 ZBTB6 BTBD7 KLHL11 KLHL41 ZBTB2 ZBTB7A BTBD8 KLHL12 KLHL5 ZBTB20 ZBTB7B BTBD9 KLHL13 KLHL6 ZBTB21 ZBTB7CCCIN KLHL14 KLHL7 ZBTB22 ZBTB8A ENC1 KLHL15 KLHL8 ZBTB24 ZBTB8BGAN KLHL17 KLHL9 ZBTB25 ZBTB9 GMCL1 KLHL18 LZTR1 ZBTB26 ZNF131 GMCL2 KLHL2 MYNN ZBTB3GZF1 KLHL20 NACC1 ZBTB32WSGR Docket No. 65514-707.601HIC1 KLHL21 NACC2 ZBTB33ABTB1 KLHL22 PATZ1 ZBTB34

[0035] In some cases, the first moiety binds to a transcriptional repressor expressed in B cell subpopulations (FIG. 1). In some cases, the first moiety binds to PR Domain Containing 1 (PRDM1) (also known as B Lymphocyte-Induced Maturation Protein 1 (BLIMP- 1). In some cases, the first moiety binds to IRF4.

[0036] The term “modulator of gene regulation”, as used herein, refers to any agent, compound, or molecular entity that directly or indirectly affects gene expression. A “modulator of gene regulation” includes, but is not limited to “transcriptional modulator(s)”, “epigenetic modulator(s)”, “RNA-based modulator(s)”, and “chromatin modulator(s)”. The term “modulator of gene regulation(s)” encompasses both direct and indirect modulators, including small molecules, peptides, proteins, nucleic acids, and synthetic constructs, whether naturally occurring or engineered. Examples of modulators of gene regulation are provided in Table 2.

[0037] The term “transcriptional modulator(s)”, as used herein, refers to agents that influence the transcriptional activity of genes, including activators, repressors, and cofactors that interact with transcriptional machinery, transcription factors, or their associated complexes. The term “epigenetic modulator(s)”, as used herein, refers to agents that alter gene expression through modifications that do not involve changes to the DNA sequence, such modifications including, but not limited to histone modifications (e.g., acetylation, methylation, phosphorylation, ubiquitination, sumoylation, or other chemical modifications of histone proteins) and DNA modifications (e.g., methylation, hydroxymethylation, or other modifications of the DNA itself). The term “RNA-based modulator(s)”, as used herein, refers to non-coding RNAs, RNA- binding proteins, and RNA- modifying enzymes (e.g., m6A writers, erasers, and readers) that regulate gene expression epigenetically. The term “chromatin modulators”, as used herein, refers to agents that directly or indirectly alter chromatin structure to regulate gene expression, including chromatin remodelers, nucleosome positioning factors, and other components that influence DNA accessibility without necessarily imparting a heritable modification.

[0038] The modulator of gene regulation may be a transcriptional modulator protein. The transcriptional modulator protein may be any protein that can modulate transcription of a gene, including increasing or decreasing expression of a gene. In some cases, the transcriptional modulator protein may be a transcription repressor, a transcription activator, a transcription co-activator, or a transcriptionprotein recruiting protein. In some cases, the modulator of gene regulation can be an epigenetic modulator protein exhibiting enzymatic activity that results in the epigenetic modification of a target gene (e.g., DNA, such as chromosomal DNA). Epigenetic modifications can include, but are not limited to, DNA methylation and demethylation, histone modifications including methylation and demethylation (e.g., mono-, di- and tri-methylation), histone acetylation and deacetylation, histone ubiquitylation, histone phosphorylation, and histone sumoylation. In some embodiments, the modulator of gene regulation is BRD4. In some embodiments, the modulator of gene regulation is CDK9. In someWSGR Docket No. 65514-707.601embodiments, the modulator of gene regulation is p300. In some embodiments, the modulator of gene regulation is selected from Table 2.Table 2. Modulators of gene regulationCategory Examples of modulators of gene regulation LSD1, KDM6A (UTX), KDM6B (JMJD3), Histone Demethylases KDM7A, JARID1A / B / C (KDM5 family),JMJD2A-D (KDM4 family), TET1-3DNA Methylation / Demethylation DNMT1, DNMT3A, DNMT3B, TET1-3, ID AX CDK9, CDK7 (TFIIH complex), CDK8 Cyclin-Dependent Kinases(Mediator-associated kinase), CDK12 / 13 SMARCA2 (BRM), SMARCA4 (BRG1), PBRM, ARID 1 A / ARID IB, CHD3 / CHD4 (NuRD Chromatin Remodeling Complexescomplex), components of the BAF / PBAF complexMediator Complex Components MED1, MED12, MED13General Coactivators SRC- 1 / 2 / 3 (NCOA1 / 2 / 3), ASH1L Corepressors NCoR / SMRTChromatin Binding Proteins HP1 (e.g., HP1α, HP1β), SIRT1 / 2 / 6P300, CBP, MOZ / MORF (KAT6A / KAT6B), Histone AcetyltransferasesPCAF, GCN5BRD2, BRD3, BRD4, BRDT, BRD1, BRPF1 / 2 / 3, Bromodomain ProteinsATAD2, BRD9MLL1-4, EZH2 (PRC2 complex), SETD2, Histone MethyltransferasesSUV39H1 / H2, DOT1L, PRDM9MYC, NFkB, E2F, E2A, AP-1, IRF4, ER, AR, Transcription FactorsEGR2, OCT2, POU2AF1O-GlcNAc Transferase (OGT), O-GlcNAcase Enzymes regulating O-GlcNAcylation(OGA)Proteins containing an activation domain: As defined in: Ruden et al, Nature, 1991; 350(6315):250-2. doi: 10.1038 / 350250a0

[0039] In some cases, the linker is any linker as described herein. In some cases, the linker is absent such that moiety A and moiety B are directly linked to each other (e.g., a compound (CIP) of Formula (I)). In some cases, the linker is present (e.g., a compound (CIP) of Formula II). In some cases, the linker is a chemical linker. In some cases, the linker has a molecular weight of less than about 2,000 g / mol. In some cases, the linker has a molecular weight of about 50 g / moL to about 2000 g / moL. In some cases, the linker has aLogP of less than about 10. In some cases, the linker has less than about 50WSGR Docket No. 65514-707.601rotatable bonds. In some cases, the linker has a Topological Polar Surface Area (TPSA) of less than about 300. In some cases, the linker is asymmetrical, symmetrical, or a bond.

[0040] The terms “specific binding,” “specifically bind,” and the like, refer to the ability of the first and second ligands or moieties to preferentially bind directly to their corresponding first and second endogenous proteins relative to other molecules or moieties in the cell. In certain embodiments, the affinity between a given ligand or moiety and its corresponding endogenous protein when they are specifically bound to each other in a binding complex is characterized by a KD (dissociation constant) of 10E-5 M or less, 10E-6 M or less, 10E-7 M or less, 10E-8 M or less, 10E-9 M or less, 10E-10 M or less, 10E- 11 M or less, 10E- 12 M or less, 10E- 13 M or less, 10E- 14 M or less, or 10E- 15 M or less (it is noted that these values can apply to other specific binding pair interactions mentioned elsewhere in this description, in certain embodiments). First moieties, second moieties, and linkers that may be employed in embodiments of the disclosure are described in greater detail below. When provided in a cell, e.g., by contacting the cell with a compound (e.g., a CIP), the first endogenous protein (e.g., a BTB domain-containing protein (e.g., BCL6), a transcriptional repressor expressed in B cell subpopulations (e.g., PRDM1, IRF4)) and the second endogenous protein (e.g., a modulator of gene regulation (e.g., BRD4, CDK9, p300)) are spatially paired (e.g., spatially complexed) to one another via the CIP to yield a gain-of-function in the cell, e.g., as described in greater detail below.

[0041] The CIP as provided herein can bind to a plurality of different proteins (e.g., a plurality of different endogenous proteins) to spatially complex the plurality of different proteins (or form a complex with the plurality of different proteins), thereby yielding a gain-of-function in the cell that would otherwise not exist in the absence of the compound. The term “gain-of-function” as used herein refers to a function that is achieved in the presence of the CIP, which may result in the formation of a ternary complex formed between a first endogenous protein (e.g., a BTB domain- containing protein (e.g., BCL6), a transcriptional repressor expressed in B cell subpopulations (e.g., PRDM1, IRF4)), a second endogenous protein (e.g., a modulator of gene regulation (e.g., BRD4, CDK9, p300)), and a CIP of the disclosure, said gain of function would not otherwise have been achieved in the absence of the CIP. The gain-of-function is not achieved when either of the first or the second endogenous protein is not expressed in the cell, where the ternary complex cannot be formed. A non-limiting example of a gain-of-function, as used herein, is the use of the CIPs provided herein to recruit the second endogenous protein (e.g., a modulator of gene regulation (e.g., BRD4, CDK9, p300)) to a target gene such that the second endogenous protein is capable of modulating expression of the target gene in the presence of the CIP, a function the second endogenous protein would not have in the absence of the compound. In some embodiments, the second endogenous protein has substantially no effect on the expression or activity levels of the target gene. In some other embodiments, the second endogenous protein modulates the target genes in a manner opposite to that effectuated by the CIP disclosed herein. In some other embodiments, the second endogenous protein may be recruited to a target pro-apoptotic gene by a ternary complex formed between the second endogenous protein (e.g., a modulator of gene regulation (e.g., BRD4, CDK9, p300)), a first endogenous protein that binds to the target pro-apoptotic gene (e. g., a BTBWSGR Docket No. 65514-707.601domain-containing protein (e.g., BCL6), a transcriptional repressor expressed in B cell subpopulations (e.g., PRDM1, IRF4)), and the CIP, such that expression of the pro-apoptotic gene is enhanced. The number of different proteins bound by the CIP to form the ternary complex can be at least or up to about 2 different proteins, at least or up to about 3 different proteins, at least or up to about 4 different proteins, at least or up to about 5 different proteins, at least or up to about 6 different proteins, at least or up to about different 7 proteins, at least or up to about 8 different proteins, at least or up to about 9 different proteins, at least or up to about 10 different proteins, at least or up to about 15 different proteins, or at least or up to about 20 different proteins. The plurality of different proteins can be different proteins exhibiting different activities (e.g., innate or natural activities) in the cell, such as, but not limited to, binding to and regulating different genes in the cell. In some embodiments, the CIPs provided herein bind to BCL6 and at least one of BRD4, CDK9, or p300.

[0042] Conventional drug development involves the identification of a target and then the construction of ways to inhibit, degrade, or remove the RNA or gene encoding the target. This conventional means of drug development then requires that the target be largely removed. In contrast, the gain of function approach described herein uses only a fraction of the target to provide a new therapeutic function to the cell. Advantageously, the gain-of-function described herein does not require recruitment of all of the second endogenous protein present in the cell. In some instances, only a small fraction of the second endogenous protein present in the cell need be recruited to the target gene to achieve the gain-of-function. Not wishing to be bound by any particular theory, the usage of a small amount of second endogenous protein renders the subject composition more efficacious with larger therapeutic window as compared to other conventional therapeutics that require large bioavailability or exposure to be effective. In some instances, the gain-of-function may be achieved (e.g., regulation of the target gene by the second endogenous protein in the presence of the CIP, which otherwise would not be regulatable by the second endogenous protein in the absence of the CIP) by recruiting to the target gene, or by utilizing, less than or equal to about 50%, less than or equal to about 45%, less than or equal to about 40%, less than or equal to about 35%, less than or equal to about 30%, less than or equal to about 25%, less than or equal to about 20%, less than or equal to about 15%, less than or equal to about 10%, less than or equal to about 9%, less than or equal to about 8%, less than or equal to about 7%, less than or equal to about 6%, less than or equal to about 5%, less than or equal to about 4%, less than or equal to about 3%, less than or equal to about 2%, or less than or equal to about 1% of an amount of the second endogenous protein present in the cell.

[0043] In some cases, the gain-of-function may be achieved (e.g., regulation of the target gene by the second endogenous protein in the presence of the compound, which otherwise would not be regulatable by the second endogenous protein in the absence of the compound) by recruiting to the target gene, or by utilizing less than or equal to about 50% of the amount of the second endogenous protein present in the cell. In some cases, the gain-of-function may be achieved by recruiting to the target gene, or by utilizing less than or equal to about 10% of the amount of the second endogenous protein present in the cell. In some instances, the gain-of-function may be achieved by recruiting to the target gene, or by utilizing,WSGR Docket No. 65514-707.601about 1% to about 30%, about 1% to about 20%, about 1% to about 15%, or about 1% to about 10%, of the amount of the second endogenous protein present in the cell. In some cases, the gain-of-function may be achieved by recruiting to the target gene, or by utilizing, about 2% to about 20% of the amount of the second endogenous protein present in the cell. In some cases, the gain-of-function may be achieved by recruiting to the target gene, or by utilizing, about 2% to about 10% of the amount of the second endogenous protein present in the cell.

[0044] In some instances, the gain-of-function may be achieved by utilizing at least or up to about 1%, at least or up to about 2%, at least or up to about 3%, at least or up to about 4%, at least or up to about 5%, at least or up to about 6%, at least or up to about 7%, at least or up to about 8%, at least or up to about 9%, at least or up to about 10%, at least or up to about 15%, at least or up to about 20%, at least or up to about 25%, at least or up to about 30%, at least or up to about 35%, at least or up to about 40%, at least or up to about 45%, at least or up to about 50%, at least or up to about 55%, at least or up to about 60%, at least or up to about 65%, at least or up to about 70%, at least or up to about 75%, at least or up to about 80%, at least or up to about 85%, at least or up to about 90%, at least or up to about 95%, substantially about 100%, about 1% to about 50%, about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 2% to about 50%, about 2% to about 45%, about 2% to about 40%, about 2% to about 35%, about 2% to about 30%, about 2% to about 25%, about 2% to about 20%, about 2% to about 15%, or about 2% to about 10% of the first endogenous protein (e.g., a BTB domain-containing protein (e.g., BCL6), a transcriptional repressor expressed in B cell subpopulations (e.g., PRDM1, IRF4)) and / or the second endogenous protein (e.g., a modulator of gene regulation (e.g., BRD4, CDK9, p300)) present in the cell.

[0045] The amount of the first endogenous protein and / or second endogenous protein required to yield the gain-of-function as provided herein can be ascertained by various methods, such as, for example, chromatin immunoprecipitation (ChIP) sequencing that can identify (i) the amount of the first endogenous protein that is spatially associated with (e.g., bound to) a target gene of the second endogenous protein and / or (ii) the amount of the second endogenous protein that is spatially associated with (e. g., bound to) a target gene of the first endogenous protein. Such information can be utilized along with a total of the first endogenous protein and / or the second endogenous protein to determine a proportion (e.g., percentage) of the first endogenous protein and / or the second endogenous protein required to yield the gain-of-function.

[0046] The CIP as provided herein can bind to a plurality of different proteins (e.g., a plurality of different endogenous proteins) to spatially complex the plurality of different proteins (or form a complex with the plurality of different proteins), to yield a gain-of-function in the cell. The gain-of-function can be characterized by eliciting or promoting a characteristic in the cell (which otherwise would not be achieved in the absence of the compound). In some cases, the gain-of-function includes inducing the death of the cell, such as inducing death of the cell within at most about 5 days, at most about 4 days, at most about 3 days, at most about 2 days, at most about 1 day, at most about 18 hours, at most about 12WSGR Docket No. 65514-707.601hours, at most about 8 hours, etc., after contacting the cell with the CIP, as compared to that in absence of the CIP). In some cases, the gain-of-function includes enhancing expression or activity level of a target gene (e.g., by at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 50%, at least about 100%, at least about 200%, at least about 400%, etc., as compared to that in absence of the CIP).

[0047] In some cases, the CIP can mediate the gain-of-function with an EC50 (e.g., for eliciting the characteristic in the cell) of less than or equal to about 10 micromolar, less than or equal to about 5 micromolar, less than or equal to about 2 micromolar, less than or equal to about 1 micromolar, less than or equal to about 900 nanomolar, less than or equal to about 800 nanomolar, less than or equal to about 700 nanomolar, less than or equal to about 600 nanomolar, less than or equal to about 500 nanomolar, less than or equal to about 400 nanomolar, less than or equal to about 300 nanomolar, less than or equal to about 200 nanomolar, less than or equal to about 100 nanomolar, less than or equal to about 90 nanomolar, less than or equal to about 80 nanomolar, less than or equal to about 70 nanomolar, less than or equal to about 60 nanomolar, less than or equal to about 50 nanomolar, less than or equal to about 40 nanomolar, less than or equal to about 30 nanomolar, less than or equal to about 20 nanomolar, less than or equal to about 10 nanomolar, less than or equal to about 9 nanomolar, less than or equal to about 8 nanomolar, less than or equal to about 7 nanomolar, less than or equal to about 6 nanomolar, less than or equal to about 5 nanomolar, less than or equal to about 4 nanomolar, less than or equal to about 3 nanomolar, less than or equal to about 2 nanomolar, less than or equal to about 1 nanomolar, less than or equal to about 0.9 nanomolar, less than or equal to about 0.8 nanomolar, less than or equal to about 0.7 nanomolar, less than or equal to about 0.6 nanomolar, less than or equal to about 0.5 nanomolar, less than or equal to about 0.4 nanomolar, less than or equal to about 0.3 nanomolar, less than or equal to about 0.2 nanomolar, or less than or equal to about 0.1 nanomolar. In an example, the CIP can mediate the gain-of-function with an EC50 of less than or equal to about 1 micromolar. In another example, the CIP can mediate the gain-of-function with an EC50 of less than or equal to about 500 nanomolar. In another example, the CIP can mediate the gain-of-function with an EC50 of less than or equal to about 200 nanomolar. In another example, the CIP can mediate the gain-of-function with an EC50 of less than or equal to about 100 nanomolar. In another example, the CIP can mediate the gain-of-function with an EC50 of less than or equal to about 50 nanomolar. In another example, the CIP can mediate the gain-of-function with an EC50 of less than or equal to about 20 nanomolar. The term “EC50”, as used herein in the context of an in vitro or in vivo assay, generally refers to the concentration of a test moiety (e.g., a CIP as described herein, such as a small molecule) that induces a response (e.g., a desired response or a target response) that is about 50% of the maximal response (i.e., halfway between the maximal response and a baseline in absence of the test moiety).

[0048] The CIP as provided herein can bind to a plurality of different proteins (e.g., a plurality of different endogenous proteins) to spatially complex the plurality of different proteins (or form a complex with the plurality of different proteins), to yield a gain-of-function in the cell. In some cases, the CIPs provided herein spatially complex a BTB domain- containing protein (e.g., BCL6) or a transcriptionalWSGR Docket No. 65514-707.601repressor expressed in B cell subpopulations (e.g., PRDM1, IRF4) with a modulator of gene regulation (e.g., BRD4, CDK9, p300). The gain-of-function can be characterized by modulated (e.g., enhanced) expression or activity level of a target gene (e.g., a proapoptotic gene) by the second endogenous protein which, in the absence of the CIP, does not substantially affect expression or activity levels of the target gene). In some cases, the gain-of-function can be characterized in that the expression or activity level of the target gene (e.g., a proapoptotic gene) is enhanced by at least or up to about 1%, at least or up to about 2%, at least or up to about 5%, at least or up to about 10%, at least or up to about 15%, at least or up to about 20%, at least or up to about 30%, at least or up to about 40%, at least or up to about 50%, at least or up to about 60%, at least or up to about 70%, at least or up to about 80%, at least or up to about 90%, at least or up to about 100%, at least or up to about 150%, at least or up to about 200%, at least or up to about 300%, at least or up to about 400%, at least or up to about 500%, at least or up to about 0.1-fold, at least or up to about 0.5-fold, at least or up to about 1 -fold, at least or up to about 2-fold, at least or up to about 3-fold, at least or up to about 4-fold, at least or up to about 5-fold, at least or up to about 10-fold, at least or up to about 15-fold, at least or up to about 20-fold, at least or up to about 30-fold, at least or up to about 40-fold, at least or up to about 50-fold, at least or up to about 60-fold, at least or up to about 70-fold, at least or up to about 80-fold, at least or up to about 90-fold, at least or up to about 100-fold, at least or up to about 110-fold, at least or up to about 120-fold, at least or up to about 130-fold, at least or up to about 140-fold, at least or up to about 150-fold, at least or up to about 200-fold, or at least or up to about 500-fold, as compared to that in the absence of the CIP.

[0049] In some cases, the CIP can comprise a plurality of different moi eties exhibiting specific binding to a plurality of different endogenous proteins. The plurality of different endogenous proteins can comprise a BTB domain- containing protein (e.g., BCL6) or a transcriptional repressor expressed in B cell subpopulations (e.g., PRDM1, IRF4) that effects reduced (or enhanced) expression of a first target gene and (ii) a modulator of gene regulation (e.g., BRD4, CDK9, p300) that effects enhanced (or reduced) expression of a second target gene. In such scenarios, the gain-of-function achieved by the CIP can be characterized by changing (e.g., reversing or inducing an opposite effect on) the expression profiles of the first target gene and / or the second target gene.

[0050] In some cases, the gain-of-function can be characterized in that (1) the expression of the first target gene is enhanced by at least or up to about 1%, at least or up to about 2%, at least or up to about 5%, at least or up to about 10%, at least or up to about 15%, at least or up to about 20%, at least or up to about 30%, at least or up to about 40%, at least or up to about 50%, at least or up to about 60%, at least or up to about 70%, at least or up to about 80%, at least or up to about 90%, at least or up to about 100%, at least or up to about 150%, at least or up to about 200%, at least or up to about 300%, at least or up to about 400%, at least or up to about 500%, at least or up to about 0.1 -fold, at least or up to about 0.5-fold, at least or up to about 1-fold, at least or up to about 2-fold, at least or up to about 3 -fold, at least or up to about 4-fold, at least or up to about 5-fold, at least or up to about 10-fold, at least or up to about 15-fold, at least or up to about 20-fold, at least or up to about 30-fold, at least or up to about 40-fold, at least or up to about 50-fold, at least or up to about 60-fold, at least or up to about 70-fold, at least or up to about 80-WSGR Docket No. 65514-707.601fold, at least or up to about 90-fold, at least or up to about 100-fold, at least or up to about 110-fold, at least or up to about 120-fold, at least or up to about 130-fold, at least or up to about 140-fold, at least or up to about 150-fold, at least or up to about 200-fold, or at least or up to about 500-fold.

[0051] In some cases, the gain-of-function achieved by the compositions and methods provided herein can be characterized by modulated (e.g., enhanced) expression or activity levels of a target gene (e.g., a proapoptotic gene) (e.g., by the second endogenous protein (e.g., a modulator of gene regulation (e.g., BRD4, CDK9, or p300)) in the presence of the CIP, where the second endogenous protein has substantially no effect on expression or activity levels of the target gene in the absence of the CIP). In some other cases, the second endogenous protein modulates the target genes in a manner opposite to that effectuated by the CIP disclosed herein. In some cases, the expression or activity levels of a target gene may be modulated (e.g., enhanced or reduced) in less than or equal to about 16 hours, in less than or equal to about 15 hours, in less than or equal to about 14 hours, in less than or equal to about 13 hours, in less than or equal to about 12 hours, in less than or equal to about 11 hours, in less than or equal to about 10 hours, in less than or equal to about 9 hours, in less than or equal to about 8 hours, in less than or equal to about 7 hours, in less than or equal to about 6 hours, in less than or equal to about 5 hours, in less than or equal to about 4 hours, in less than or equal to about 3 hours, in less than or equal to about 2 hours, or in less than or equal to about 1 hour, after contacting the cell with the compound, as compared to that in the absence of the compound. In an example, the expression or activity levels of a target gene may be modulated (e.g., enhanced or reduced) in less than or equal to about 16 hours after contacting the cell with the compound, as compared to that in the absence of the compound. In another example, the expression or activity levels of a target gene may be modulated (e.g., enhanced or reduced) in less than or equal to about 8 hours after contacting the cell with the compound, as compared to that in the absence of the compound.

[0052] Any modulation of expression level of a target gene as provided herein can be induced or observed (e.g., via experimentation) in less than or equal to about 48 hours, less than or equal to about 42 hours, less than or equal to about 36 hours, less than or equal to about 30 hours, less than or equal to about 24 hours, less than or equal to about 18 hours, less than or equal to about 12 hours, less than or equal to about 10 hours, less than or equal to about 9 hours, less than or equal to about 8 hours, less than or equal to about 7 hours, less than or equal to about 6 hours, less than or equal to about 5 hours, less than or equal to about 4 hours, less than or equal to about 3 hours, less than or equal to about 2 hours, less than or equal to about 1 hour, less than or equal to about 45 minutes, less than or equal to about 30 minutes, less than or equal to about 20 minutes, less than or equal to about 15 minutes, or less than or equal to about 10 minutes.

[0053] In some cases, the protein (e.g., first and / or second endogenous protein) that is bound to the CIP as provided herein may be a functional protein, e.g., exhibiting its innate or natural function (e.g., binding, associating with, and / or regulating expression of a target gene) prior to complexing with the CIP. Thus, at least a portion of such activity may be reduced (e.g., by at least or up to about 1%, at least or up to about 2%, at least or up to about 5%, at least or up to about 10%, at least or up to about 15%, atWSGR Docket No. 65514-707.601least or up to about 20%, at least or up to about 25%, at least or up to about 30%, at least or up to about 40%, at least or up to about 50%, at least or up to about 60%, at least or up to about 70%, at least or up to about 80%, at least or up to about 90%, at least or up to about 95%, or substantially about 100%) upon complexing with the CIP.

[0054] The nature of the first and second moieties (also referred to herein as first and second ligands), as well as the linker components (when used), of the CIP compounds may vary. In any given CIP compound, the first and second ligands are chosen based on the nature of the corresponding first endogenous protein (e.g., a BTB domain- containing protein (e.g., BCL6), a transcriptional repressor expressed in B cell subpopulations (e.g., PRDM1, IRF4)) and second endogenous protein (e.g., a modulator of gene regulation (e.g., BRD4, CDK9, p300)), to which the moieties bind. Specificity of activity with respect to a particular cell type may be provided through selection of the first and second ligands of the CIP, which can be configured to recruit the first endogenous protein and the second endogenous protein in a manner that provides for desired cell or conditional specificity. For example, CIPs can be engineered to induce proximity of a first endogenous protein and a second endogenous protein that are primarily present in a target cell of interest, such that the CIP exhibits highly selective activity for that cell. The selectivity of a given CIP may be described by the following formula:

[0055] (selectively of expression of the first endogenous protein) x (selectively of expression of the second endogenous protein) x (genomic specificity of the first endogenous protein) = selectivity of induced activity

[0056] Examples of first and second moieties (e.g., A and B in the CIP formula provided herein, also referred to herein as first and second ligands) that may be employed in various CIPs are reviewed in greater detail below. Suitable first and second moieties, as well as methods of identifying the same, that may be employed in CIPs of embodiments of the disclosure are also provided in PCT application serial no. PCT / US2021 / 058231, published as WO 2022 / 098989; the disclosure of which is herein incorporated by reference.Linkers

[0057] As described above, the present disclosure provides compounds (e.g., CIPs), in some embodiments, having two ligands, e.g., a BTB domain-containing protein ligand (e.g., a BCL-6 (B-cell lymphoma 6) ligand, a transcriptional repressor expressed in B cell subpopulations ligand (e.g., a PRDM1 ligand, anIRF4 ligand) and a second ligand (e.g., a modulator of gene regulation ligand (e.g., a BRD4 (bromodomain- containing 4) ligand, a CDK9 ligand, and / or a p300 ligand)), that are covalently bonded through a linker. When employed, any convenient linker may be employed to link the first and second ligands to each other. Linkers of interest are linkers that provide for a stable association of the first and second ligands in a manner such that the first and second ligands are capable of specifically binding to their respective endogenous factors in the cell. As the linker provides for stably associating the first and second ligands with each other, the first and second ligands do not dissociate from each other under cellular conditions, e.g., conditions at the surface of a cell, conditions inside of a cell, etc. Linkers may be provided for stable association of the first and second ligands using any convenient binding, suchWSGR Docket No. 65514-707.601as covalent or non-covalent binding, where in some instances the linker component is covalently bound to both the first and second ligands. Linking protocols of interest include, but are not limited to, addition reactions, elimination reactions, substitution reactions, pericyclic reactions, photochemical reactions, redox reactions, radical reactions, reactions through a carbene intermediate, metathesis reaction, among other types of bond-forming reactions. In some embodiments, the linkers employ reactive linking chemistry such as where reactive linker pairs (e.g., as provided by moieties on the ligands and linkers) include, but are not limited to: maleimide / thiol; thiol / thiol; pyridyldithiol / thiol; succinimidyl iodoacetate / thiol; N-succinimidylester (NHS ester), sulfodicholorphenol ester (SDP ester), or pentafluorophenyl-ester (PFP ester) / amine; bissuccinimidylester / amine; imidoesters / amines; hydrazine or amine / aldehyde, dialdehyde or benzaldehyde; isocyanate / hydroxyl or amine; carbohydrate — periodate / hydrazine or amine; diazirine / aryl azide chemistry; pyridyldithiol / aryl azide chemistry; alkyne / azide; carboxy-carbodiimide / amine; amine / Sulfo-SMCC (Sulfosuccinimidyl 4-[N-maleimidomethyl] cyclohexane- l-carboxylate) / thiol and amine / BMPH (N-[ -Maleimidopropionic acid]hydrazide. TFA) / thiol; azide / triarylphosphine; nitrone / cyclooctyne; azide / tetrazine and formylbenzamide / hydrazino-nicotinamide. In certain embodiments, a linker employs a cycloaddition reaction, such as a [1+2] -cycloaddition, a [2+2] -cycloaddition, a [3+2] -cycloaddition, a [2+4]-cycloaddition, a [4+6] -cycloaddition, or cheleotropic reactions, including linkers that undergo a 1,3-dipolar cycloaddition (e.g., azide- alkyne Huisgen cycloaddition), a Diels-Alder reaction, an inverse electron demand Diels Alder cycloaddition, an ene reaction or a [2+2] photochemical cycloaddition reaction. In some embodiments, the linker may include an alkyl chain, an alkoxy chain, an alkenyl chain or an alkynyl chain, where the number of carbon atoms in the chain may vary, ranging in some instances from 2 to 25, such as 5 to 20, where one or more carbon atoms are replaced with NH or CH3-N as reactive functionalities for covalent bonding.

[0058] In some instances, the linker is selected from a group having the following, where n refers to the total number of carbon or carbon- substituent atoms which may be present, sub-counted by k, m, and / or p:

[0059] In some instances, the linker is selected from a group comprising the following, where n refers to the total number of carbon or carbon-substituent atoms which may be present, sub-counted by k, m, and / or p:

[0060] a) A Cn alkyl chain, L, including the case where one or more carbon atoms are replaced with NH or CH3-N

[0061] b) A Cn alkoxy chain, L, including the case where one or more carbon atoms are replaced with NH or CH3-N

[0062] c) A Cn alkenyl or alkenyloxy chain, L, including the case where one or more carbon atoms are replaced with NH or CH3-N

[0063] d) A Cn alkynyl or alkynyloxy chain, L, including the case where one or more carbon atoms are replaced with NH or CH3-N

[0064] e) L1-Ar-L2or L1-Het-L2. where L1and L2can be a bond, alkenyl, alkynyl, alkynyloxy, alkenyloxy, alkoxy, or alkyl chain, e.g., of 1-10 atoms, that are either carbon or optionally substitutedWSGR Docket No. 65514-707.601nitrogens, such as CH2N(H)CH2, CH2OCH2, C5H10OCH2, and others; Ar is a 6 membered optionally substituted aryl; and Het is a 4 to 6 membered heterocycloalkyl or a 9 to 10 membered spirocyclic bicyclic heterocycloalkyl or a 3 to 6 membered optionally substituted heteroaryl.

[0065] In some embodiments, the linker includes a C(l-16) alkyl chain. In some instances, the linker includes a C(l-16) alkyl chain, wherein one or more of the methylene groups is replaced by NH or CH3-N. In some instances, the linker includes a C( 1 - 16) alkoxy chain. In some instances, the linker includes a C(l-16) alkoxy chain, wherein one or more of the methylene groups is replaced by NH or CH3-N. In certain instances, the linker includes a L1-Cyclo-L2. L1-HeteroCyclo-L2. L1-Ar-L2or L1-Het-L2. where L1and L2can be a bond, alkenyl, alkynyl, alkynyloxy, alkenyloxy, alkoxy, or alkyl chain, where:cyclo is a C(3-8) cycloalkyl or substituted C(3-8) cycloalkyl;heterocyclo is a C(3-8) heterocycloalkyl or substituted C(3-8) heterocycloalkyl;Ar is an aryl group or substituted aryl group; andHet is a heteroaryl group or substituted heteroaryl group.In certain embodiments, the linker is selected from:H 4H 1^^Y" Y r^ Y10 00L ” J p[n Y nMj.O0r 0H OO 0H < Y-Zn 000WSGR Docket No. 65514-707.601

[0066] where m, n and p are independently selected from 0 or an integer of from 1-12.

[0067] Suitable linkers that may be employed in embodiments of the present disclosure are further described in International Patent Publication Nos. W02020219650 and WO2017185023, as well as U. S. Patent No.10,532,103 and United States Patent Application Publication No. 20190111143; the disclosures of which are herein incorporated by reference.

[0068] In some embodiments, linkers of interest include those such as described in International Patent Publication No. WO2020 / 264499, the disclosure of which is herein incorporated by reference. For example, the linker may be selected from:WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.60100 (34), O O (35),O (42),H / t3VN0 (46), O OWSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601oo 0 O (140),WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601

[0069] In some embodiments, the linker suitable for use in the CIPs of the present disclosure are provided in U. S. Publication Number 2019 / 0076540A1, which is herein incorporated by reference for its disclosure of said linkers.

[0070] In some embodiments, the linker suitable for use in CIPs of the present disclosure can include one or more members selected from the following:WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601

[0071] In some embodiments, the Linker is selected from the group consisting of: Formula LI, Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI, and Formula LVII:WSGR Docket No. 65514-707.601(LI)(LII)(LIII)(LIV)(LV)(LVI)(LVII)wherein:X[and X2are independently selected from bond, NH, NR25, CFb, CHR25, C(R25)2, O, and S; R20, R2i, R22, R23. and R24are independently selected from bond, alkyl, — C(O) - C(O)O — -, — OC(O)--, --C(O)alkyl, — C(O)Oalkyl, --C(S)--. SO;. --S(O)--, --C(S)--, < iO}XI I. — NHC(O)--, --N(alkyl)C(O>--, --C(O)N(alkyl)-, O. S. XII. --N(dkyl)-, Cl =( O R'N. CH-; CH< XH ). C 1 li M<":;<i. C< () -R26)alkvl-, NHR25)alkyh, C{ XI ioalkO-. — C(- XR'‘2)alkvl~, GR'lc). -alkyl(R27)~alkyl(R2S)^, ~~C(R27R28)^ _ p(O)(OR26)O—, — P(O)(OR26)— XI K'lOiX! I. X- R';)( I ())X< 1. —WSGR Docket No. 65514-707.601N(H)C(O)N(R25)—, polyethylene glycol, poly (lactic-co-gly colic acid), alkene, haloalkyl, alkoxy, and alkyne;or R20, R21, R22. R23, and R24can in addition to those above be independently selected from heteroaryl alkyl, rayl, arylalkyl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, polypropylene glycol, lactic acid, glycolic acid, carbocycle, or — O — (CHi -n — O —. ------ NH-- (CHb — - NH —, — NH — (CH2)i..i2--€)--, or O (CH.-b.:.- NH.. S 0. O K H.-},.:.- S. S (CH.-i;.12 — S —, — S — (CH2.)i-i2 — NH —, — NH — (CHOi-i? — S —, (and wherein the 1-12 can be independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and wherein one or more of the CH?, or NH can be modified by substitution of a H for a methyl, ethyl, cyclopropyl, F (if on carbon), etc., as described herein), and optionally, a heteroatom, heteroalkyl, aryl, heteroaryl or cycloaliphatic group is interspersed in the chain).Certain nonlimiting examples include — O — CH(CHj) — CH(CH3)CH--0 —, — O — CH? — CH(CH3)CH--O--, O CHlCl H CH.-CH O. etc.each of which R20, R21, R22, R23, and R24is optionally substituted with one or more substituents selected from R!01or alternatively as described herein;R25is selected at each instance from: alkyl, --C(O)H, --C(O)OH, --C(O)alkyl, --C(O)Oalkyl, alkenyl, or alk ny 1 or alternatively can be aliphatic, heteroaliphatic, aryl, heteroaryl or heterocyclic;R26is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, and alkyne; or in addition to these can also be selected from aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic;R27and R28are independently selected from hydrogen, alkyl, amine, or together with the carbon atom to which they are attached, form C(O), CIS), C— CH?, a Cs-Cs spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O, or form a 1 or 2 carbon bridged ring;R101is independently selected at each occurrence from hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxyl, and, heteroaryl, heterocycle, aryl alkyd, heteroarylalkyl, heterocycloalkyl, aryl oxy', heteroaryloxy, CN, --COOalkyl, COOH, NO?, F, Cl, Br, I, CF3, NH?., NHalkyl, N(alkyl)2, NR2SR2S, NHR25, aliphatic, heteroaliphatic, and COR4; andR4is selected from hydrogen, alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclic, hydroxyl, alkoxy, amine, --NHalkyl, or — Nalkyl?.;In an additional embodiment, the Linker may be selected from the group consisting of: Formula LV1II, LIX. and LX:WSGR Docket No. 65514-707.601(LX)wherein each variable is as it is defined in Formula LI. In alternative embodiments of LVIII, LIX and LX, a carbocyclic ring is used in place of the heterocycle.

[0072] The following are non-limiting examples of Linkers that can be used in this disclosure. As certain non-limiting examples, Formula LI, Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI, or Formula LVII include:WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601

[0073] In some embodiments, the Linker may be selected from:WSGR Docket No. 65514-707.601

[0074] In some embodiments, the Linker may be selected from:WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601

[0075] In some embodiments, X1may be attached to the first moiety and / or the second moiety (of a compound of the disclosure). In other embodiments, X2may be attached to the first moiety and / or the second moiety (of a compound of the disclosure).

[0076] Non-limiting examples of moieties of R20, R21, R22, R23, and R24 include:WSGR Docket No. 65514-707.601o oo

[0077] Additional non-limiting examples of moieties of R20, R21, R22, R23, and R24include:WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601o o X^oY XAXWSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601o

[0078] Additional non-limiting examples of moieties of R20, R21, R22, R23, and R24include:WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601

[0079] In some embodiments, the Linker group may be an optionally substituted (poly)ethylene glycol having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, ethyleneglycol units, or optionally substituted alkyl groups interspersed with optionally substituted, O, N, S, P or Si atoms. In some embodiments, the Linker may be flanked, substituted, or interspersed with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. In some embodiments, the Linker may be asymmetric or symmetrical. In some embodiments, the Linker may be a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, from 1 to about 10 ethylene glycol units, about 2 about 6 ethylene glycol units, about 2 to about 5 ethylene glycol units, or about 2 to about 4 ethylene glycol units. In any of the embodiments of the compounds described herein, the Linker group may be any suitable moiety as described herein.WSGR Docket No. 65514-707.601

[0080] In some embodiments, the Linker may be selected from:— NR61(CH2)ni -(lower alkyl)-, — NR61(CH2)ni-(lower alkoxyl)-,— NR61(CH2)ni -(lower alkoxyl)-OCH2 —, — NR61(CH2)ni-(lower alkoxyl) -(lower alkyl)-OCH2 —, — NR61(CH2)ni-(cycloalkyl)-(lower alkyl)-OCH2 —, — NR61(CH2)ni-(heterocycloalkyl)-,— NR61(CH2CH2O)ni-(lower alkyl)-0 — CH2 —, — NR61(CH2CH2O)ni-(heterocycloalkyl)-O — CH2—, — NR61(CH2CH2O)ni-Aryl-O— CH2—, — NR61(CH2CH2O)ni-(heteroaryl)-O— CH2—,— NR61(CH2CH2O)ni-(cycloalkyl)-O-(heteroaryl)-O — CH2—,— NR61(CH2CH2O)ni-(cycloalkyl)-O-Aryl-O— CH2—,— NR61(CH2CH2O)ni-(lower alkyl)— NH-Aryl-O— CH2—,— NR61(CH2CH2O)ni-(lower alkyl)-O-Aryl-CH2,— NR61(CH2CH2O)n-cycloalkyl-O-Aryl-, — NR61(CH2CH2O)n-cycloalkyl-O-heteroaryl-,— NR61(CH2CH2)ni-(cycloalkyl)-O-(heterocycle)-CH2,— NR61(CH2CH2)ni-(heterocycle)-(heterocycle)-CH2, and — NR61-(heterocycle)-CH2;wherein nl is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; andR61is H, methyl, or ethyl.

[0081] In some embodiments, the Linker may be selected from:— N(R61)— (CH2)mi— O(CH2)n2— O(CH2)oi— O(CH2)PI— O(CH2)qi— O(CH2)ri— OCH2—,— O— (CH2)mi— O(CH2)n2— O(CH2)oi— O(CH2)PI— O(CH2)qi— O(CH2)H— OCH2—,— O— (CH2)mi— O(CH2)n2— O(CH2)oi— O(CH2)PI— O(CH2)qi— O(CH2)H— O—;— N(R61)— (CH2)mi— O(CH2)n2— O(CH2)oi— O(CH2)PI— O(CH2)qi— O(CH2)ri— O—;— (CH2)mi— O(CH2)n2— O(CH2)oi— O(CH2)pi— O(CH2)qi— O(CH2)ri— O—;— (CH2)mi— O(CH2)n2— O(CH2)oi— O(CH2)pi— O(CH2)qi— O(CH2)ri— OCH2—;— O(CH2)mi— O(CH2)n2O(CH2)piO(CH2)qiOCH2—;— O(CH2)miO(CH2)n2O(CH2)piO(CH2)qiOCH2—; whereinml, n2, ol, pl, ql, and rl are independently 1, 2, 3, 4, or 5; andR61is H, methyl, or ethyl.

[0082] In some embodiments, the Linker may be selected from:WSGR Docket No. 65514-707.601O(CH2)mlO(CH2)„2O(CH2)J,1O(CH2)92OCH2O(CH2)mlO(CH2)„2O(CH2)J,1O(CH2)92OCH.WSGR Docket No. 65514-707.601wherein m1, n2, o1, p1, q2, and r1 are independently 1, 2, 3, 4, or 5.

[0083] In some embodiments, the Linker may be selected from:WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601wherein R71is — O —, l. — NMe, — Nalkyl, N(aliphatic), — N(heteroaliphatic).

[0084] In some embodiments, the Linker can be a nonlinear chain, and can be, or include, aliphatic or aromatic or heteroaromatic cyclic moieties.

[0085] In some embodiments, the Linker may include contiguous, partially contiguous, or noncontiguous ethylene glycol unit groups ranging in size from about 1 to about 12 ethylene glycol units, about 1 to about 10 ethylene glycol units, about 2 to about 6 ethylene glycol units, about 2 to about 5WSGR Docket No. 65514-707.601ethylene glycol units, about 2 to about 4 ethylene glycol units, for example, 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units.

[0086] In some embodiments, the Linker may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or fluorine substituents. In another embodiment, the Linker may be perfluorinated. In yet another embodiment, the Linker may be a partially or fully fluorinated poly ether. Nonlimiting examples of fluorinated Linkers include:WSGR Docket No. 65514-707.601FProviding the compound of the disclosure (e.g., CIP) in the Cell

[0087] The present disclosure provides providing a CIP of the disclosure into a cell, e.g., as described above, in a manner sufficient to induce proximity of the first endogenous protein (e.g., a BTB domaincontaining protein, a transcriptional repressor expressed in B cell subpopulations) and the second endogenous protein (e.g., a modulator of gene regulation), e.g., as described above. Any convenient protocol for providing the CIP compound in the cell may be employed. The particular protocol that isWSGR Docket No. 65514-707.601employed may vary, e.g., depending on whether the target cell is in vitro or in vivo. In certain instances, the CIP compound is provided in the cell by contacting the cell with the CIP compound. For in vitro protocols, contact of the CIP compound with the target cell may be achieved using any convenient protocol. For example, target cells may be maintained in a suitable culture medium, and the CIP compound introduced into the culture medium as described specifically in the figures.

[0088] For in vivo protocols, any convenient administration protocol may be employed. The CIP can be incorporated into a variety of formulations, e.g., pharmaceutically acceptable vehicles (also referred to herein as pharmaceutical delivery vehicles or carriers), for therapeutic administration. This can be done by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments (e.g., skin creams), solutions, suppositories, injections, inhalants and aerosols. As such, administration of the agents (e.g., compounds of the disclosure) can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intratracheal, intravenous, intravesical, subcutaneous, intramuscular, etc., administration. In pharmaceutical dosage forms, the CIPs may be administered alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds. The following examples are illustrative and not limiting. In some cases, the compounds of the disclosure can be formulated and / or administered in such a way that they can cross the blood-brain barrier.

[0089] For oral preparations, the CIPs of the disclosure can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.

[0090] The CIPs of the disclosure can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.

[0091] The CIPs of the disclosure can be utilized in aerosol formulation to be administered via inhalation. The compounds of the present disclosure can be formulated into pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen and the like.

[0092] Furthermore, the CIPs of the disclosure can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. The compounds of the present disclosure can be administered rectally via a suppository. The suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.WSGR Docket No. 65514-707.601

[0093] Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition containing one or more inhibitors. Similarly, unit dosage forms for injection or intravenous administration may comprise the inhibitor(s) in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptablecarrier.

[0094] The term "unit dosage form," as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of compounds of the present disclosure calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle. The specifications for the novel unit dosage forms of the present disclosure depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in thehost.

[0095] The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Moreover, pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.

[0096] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compound, the nature of the delivery vehicle, and the like. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means.

[0097] In those embodiments where an effective amount of an active agent (e.g., a compound of the disclosure) is administered to a living subject, the amount or dosage is effective when administered for a suitable period of time, such as one week or longer, including two weeks or longer, such as 3 weeks or longer, 4 weeks or longer, 8 weeks or longer, etc., so as to evidence a desired therapeutic effect. For example, an effective dose is the dose that, when administered for a suitable period of time, such as at least about one week, and maybe about two weeks, or more, up to a period of about 3 weeks, 4 weeks, 8 weeks, or longer, will results in a desired therapeutic effect. In some instances, an effective amount or dose of active agent (e.g., a compound of the disclosure) will not only slow or halt the progression of the disease condition but will also induce the reversal of the condition, i. e., will cause an improvement one or more symptoms of the condition. For example, in some instances, an effective amount is the amount that when administered for a suitable period of time, usually at least about one week, and maybe about two weeks, or more, up to a period of about 3 weeks, 4 weeks, 8 weeks, or longer will improve one or more symptoms of a subject suffering from a disease condition, where the magnitude of improvement (e.g., as measured using a suitable protocol with relevant control) may vary, for example 1.5 -fold, 2-fold, 3-fold, 4-fold, 5-fold, in some instances 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold or more.

[0098] In certain embodiments, the methods include removing the CIP from the cell at some point after provision of the CIP. Removal of the CIP from the cell may be accomplished using any convenient protocol, e.g., by removing the CIP from the medium in which the cell is present, by ceasingWSGR Docket No. 65514-707.601administration of the CIP to the animal comprising the cell, by contacting the cell with an inhibitor of the CIP induced proximity, by contacting the cells with a molecule that displaces the CIP and binds to only one of the first endogenous protein or the second endogenous protein, etc. One specific type of inhibitor of the action of the CIP would be a one-sided molecule consisting of the ligand for either the first endogenous protein or the second endogenous protein without the linker or other moiety.

[0099] As summarized above, the disclosure further provides methods of inducibly modulating transcription of a target gene. In a non-limiting example, the target gene is a pro-apoptotic gene. As described above, proapoptotic genes are genes the expression products of which promote or cause apoptosis, programmed cell death that occurs in multicellular organisms, which may be characterized by a variety of cell changes, such as blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation, and global mRNA decay, and death. Specific proapoptotic genes of interest for transcription that may be enhanced in embodiments of the disclosure include, but are not limited to: PUMA (BBC3), BIM (BCL2L11), BID, BAX, BAK, BOK, BAD, HRK, BI BMF, and NOXA, and the like. In such instances, the magnitude of enhancement may vary, where examples include from substantially no to some expression, and in some instances the magnitude may be 2-fold or greater, such a 5-fold or greater, including 10-fold or greater.

[0100] In some instances, the cell is a B cell. In some embodiments, the B cell is a B cell present in a germinal center. In some embodiments, the B cell is a B cell present in an active, a hyperactive, or an ectopic germinal center. In some cases, the B cell is a plasma cell (or plasma B cell). In some embodiments, the B cell is present in a subject having an autoimmune disease or disorder. In some embodiments, the autoimmune disease or disorder is selected from the group consisting of: rheumatoid arthritis (RA), Sjogren’s syndrome (SS), immunoglobulin G4-related disease (IgG4-RD), juvenile arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, autoimmune thyroid disease (i.e. Graves Disease), multiple sclerosis, autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), Evan’s syndrome, systemic lupus erythematosus (SLE), dermatomyositis, scleroderma, organ rejection, Crohn’s disease, myasthenia gravis, diabetes type 1, diabetes type 2, Reiter’s syndrome, Neuromyelitis optica spectrum disorder (NMOSD), Pemphigus vulgaris, Anti-GBM (Goodpasture) disease, acquired hemophilia A, immune-mediated (acquired) TTP, seronegative enthesopathy and arthropathy (SEA) syndrome, prothrombotic autoantibody syndromes such as antiphospholipid syndrome (APS), psoriasis, and atopic dermatitis. The cell may be a cell expressing both a BTB domain- containing protein (e.g., BCL6) or a transcriptional repressor expressed in B cell subpopulations (e.g., PRDM1, IRF4) and a modulator of gene regulation (e.g., BRD4, CDK9, and / or p300), such as a B cell, a B cell of a germinal center, a B cell of an active, a hyperactive, or an ectopic germinal center, or a plasma cell.

[0101] As summarized above, the present disclosure further provides methods of inducibly modulating transcription of a target gene. Such methods include providing a CIP in a cell containing BCL6 and a second endogenous protein selected from BRD4, CDK9, and / or p300 e.g., as described above, under conditions sufficient to modulate transcription of the target gene. The CIP and cell may be as described above. The transcription modulation may vary. In some instances, the modulating includes enhancingWSGR Docket No. 65514-707.601transcription of the gene, e.g., where the gene is beneficial with respect to the disease condition, e.g., by enhancing a desired activity in the cell, such as increasing expression of a proapoptotic gene where death of the cell is desired. In such instances, the magnitude of enhancement may vary, where examples include from substantially none to some expression, and in some instances the magnitude may be 2 -fold or greater, such as 5-fold or greater, including 10-fold or greater.

[0102] In some instances, the cell is a cell of a subject diagnosed with, having, or suspected of having an autoimmune disease or disorder, e.g.,, a cell obtained from such a subject or a cell that is part of such a subject. In some embodiments, the autoimmune disease or disorder is selected from the group consisting of: rheumatoid arthritis (RA), Sjogren’s syndrome (SS), immunoglobulin G4-related disease (IgG4-RD), juvenile arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, autoimmune thyroid disease (i.e. Graves Disease), multiple sclerosis, autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), Evan’s syndrome, systemic lupus erythematosus (SLE), dermatomyositis, scleroderma, organ rejection, Crohn’s disease, myasthenia gravis, diabetes type 1, diabetes type 2, Reiter’s syndrome, Neuromyelitis optica spectrum disorder (NMOSD), Pemphigus vulgaris, Anti-GBM (Goodpasture) disease, acquired hemophilia A, immune-mediated (acquired) TTP, seronegative enthesopathy and arthropathy (SEA) syndrome, prothrombotic autoantibody syndromes such as antiphospholipid syndrome (APS), psoriasis, and atopic dermatitis. The compositions and methods of the disclosure find use in the treatment of a variety of different autoimmune diseases or disorders in which the modulation of target gene transcription in a host is desired. By treatment is meant that at least an amelioration of one or more of the symptoms associated with the autoimmune disease or disorder afflicting the host is achieved, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g., symptom, associated with the autoimmune disease or disorder being treated. As such, treatment also includes situations where the autoimmune disease or disorder, or at least symptoms associated therewith, are completely inhibited, e.g., prevented from happening, or stopped, e.g., terminated, such that the host no longer suffers from the autoimmune disease or disorder, or at least the symptoms that characterize the autoimmune disease or disorder.

[0103] Where the methods are methods of treating a subject for an autoimmune disease or disorder, the methods may further include assessing that the subject has the given autoimmune disease or disorder, e.g., so as to confirm that a given CIP is suitable for use in treating the subject for the autoimmune disease or disorder. Any convenient diagnostic protocol appropriate for the autoimmune disease or disorder may be employed, where the choice of such protocol will necessarily depend on the specific autoimmune disease or disorder to be treated.

[0104] A variety of subjects are treatable according to the subject methods. In some instances, the subjects are "mammals" or "mammalian," where these terms are used broadly to describe organisms which are within the class mammalia, including the orders carnivore (e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats), and primates (e.g., humans, chimpanzees, and monkeys). In some instances, the subjects are humans.Bromodomain-containing 4 (BRD4) LigandsWSGR Docket No. 65514-707.601

[0105] Methods of treating a subject for an autoimmune disease or disorder are provided. In some cases, the methods can include administering a CIP which links the BTB domain- containing protein (e.g., BCL6) or the transcriptional repressor expressed in B cell subpopulations (e.g., PRDM1, IRF4) with BRD4 to treat the subject for the autoimmune disease or disorder. Also provided are compositions that find use in practicing methods of the disclosure.

[0106] Suitable ligands for BRD4 include, but are not limited to, those described in U. S. Patent Nos.11,279,703; 11,267,820; 11,117,865; 11,020,404; 10,975,059; 10,738,016; 10,689,395; 10,526,291; 10,328,074; 10,300,073; 10,106,507; 10,071,129; 9,840,526; 9,814,728; 9,610,332; 9,387,231;9,266,891; 9,255,089; 9,249,161; 9,108,953, as well as those described in United States Patent Application Publication Nos. 20220185820; 20220177459; 20220119370; 20220047596; 20210355088; 20210221821; 20210147419; 20200407328; 20200405809; 20200385408; 20200339595; 20200338065; 20200255450; 20200095252; 20200046726; 20190367530; 20190381013; 20190359573; 20190292168; 20190262355; 20190055203; 20180290984; 20180282316; 20180237453; 20180050043; 20170304315; 20170226065; 20160129001; 20160075695; 20160060260; 20160031868; 20150148344; 20150148333; 20150133436; 20150087636; 20140371157; 20140336190; 20140296246; 20140296243; 20140243322; 20140243286; 20140005169; 20140044770; 20120208800; 20120157428; the disclosures of which are herein incorporated by reference.

[0107] Suitable ligands for BRD4 include, but are not limited to: JQ1, AZD5153, ABBV-075, BMS-986158, CPI-0610, GSK525762; OTX-015, PLX51107, INCB054329, INCB057643, I-BET151, RVX-208 and the like. The structures are provided below:WSGR Docket No. 65514-707.601

[0108] In some embodiments, the bromodomain- containing 4 ligand is of formula IA:where:n is an integer from 0 to 12;m is an integer from 0 to 5;p is an integer from 0 to 5;A is a 5-8 membered cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;WSGR Docket No. 65514-707.601B is a 3-12 membered cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;W is C, N, O or S;X is oxygen or sulfur, or: R3and X are taken together with their intervening atoms to form an optionally substituted 5-6 membered cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaryl alkyl, and substituted heteroarylalkyl;Y is a covalent bond, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a substituted bivalent C(l-6) hydrocarbon chain wherein one or more methylene units is optionally replaced by -NR’-, -N(R’)C(O)-, -C(O)N(R')- -N(R’)SO2-, -SO2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-;Z is -CH2, -NH, -O- or -S- - represents a single or double bond;represents a bond to the linker;each of R1, R2, R3, R4and R5is independently selected from hydrogen, halogen, hydroxyl, alkoxyl, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxy carbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, thiol, substituted thiol, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfoximine and substituted sulfoxi mine.

[0109] In some embodiments, A is a 5-membered fused heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, A is a 5 -membered fused heteroaryl ring having 2 heteroatoms independently selected from nitrogen or oxygen. In some instances, A is a 5-membered fused heteroaryl ring having 2 heteroatoms selected from nitrogen and oxygen. In some instances, A is a 5- membered fused heteroaryl ring having 2 heteroatoms independently selected from nitrogen or sulfur. In some instances, A is a 5 -membered fused heteroaryl ring having 2 heteroatoms selected from nitrogen and sulfur. In certain instances, A is selected from thiazolo, isothiazolo, oxazolo, isoxazolo, pyrazolo, and imidazolo rings. In certain instances, A is isothiazolo.

[0110] In some embodiments, A is benzo, or a 5-6 membered fused heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, A is a 5-membered fused heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 6-membered fused heteroaryl ring having 2-3 nitrogen atoms. In some instances, A is benzo. In some embodiments, A is a 5-6 membered fused heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, A is a 6 -membered fused heteroaryl ring having 1-3 nitrogen atoms. In certain instance, A is selected from pyrido, pyrimidino, pyrazino, pyridazino, andtriazino, rings. In certain instances, A is a 5 -membered fused heteroaryl ringWSGR Docket No. 65514-707.601having 1 heteroatom selected from nitrogen, oxygen, or sulfur. In certain instances, A is thieno. In certain instances, A is furano. In certain instances, A is pyrrolo.

[0111] In some embodiments, B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is phenyl. In some instances, B is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In certain instances, B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In certain instances, B is cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0112] In some embodiments, B is a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring B is a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring B is tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, or morpholinyl.

[0113] In some embodiments, B is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is 6-membered heteroaryl ring having 1-3 nitrogen atoms. In some instances, B is a 6-membered heteroaryl ring having 1 nitrogen atom. In some instances, B is a 6-membered heteroaryl ring having 2 nitrogen atoms. In some instances, B is a 6-membered heteroaryl ring having 3 nitrogen atoms.

[0114] In some embodiments, B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, B is a 5 -membered heteroaryl ring having 1 heteroatom independently selected from nitrogen, oxygen, or sulfur. In some instances, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen and oxygen. In some instances, B is a 5 -membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen and sulfur. In some instances, B is a 5 -membered heteroaryl ring having 1-3 nitrogen atoms. In certain instances, B is selected from thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0115] In some embodiments, B is a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen,WSGR Docket No. 65514-707.601oxygen, and sulfur. In some instances, B is a 5,5-fused-, 5,6-fused, or 6,6-fused saturated, partially unsaturated, or aromatic bicyclic ring. In some instances, B is a 5,5-fused, 5,6-fused, or 6,6-fused aromatic bicyclic ring. In some instances, B is a naphthalenyl, indanyl or indenyl group.

[0116] In some embodiments, B is a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 7-8 membered bicyclic saturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 7-8 membered bicyclic partially unsaturated heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 9-10 membered bicyclic saturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instance^ B is a 9-10 membered bicyclic partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, or quinuclidinyl. In some instances, B is selected from indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, 2-azabicyclo[2.2. l]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.

[0117] In some embodiments, B is a 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 5,5-fused, 5,6-fused, or 6,6-fused saturated, partially unsaturated, or aromatic bicyclic ring having 1-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur. In some instances, B is a 5,5-fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur. In certain instances, B is a 5,5-fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1-4 nitrogen atoms. In certain instances, B is a 5,6-fused heteroaryl ring having 1-4 nitrogen atoms. In certain instances, B is pyrrolizinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, imidazopyridinyl, indazolyl, purinyl, cinnolinyl, quinazolinyl, phthalazinyl, naphthridinyl, quinoxalinyl, thianaphtheneyl, or benzofuranyl. In certain instances, B is selected from an indolizinyl, purinyl, naphthyridinyl, or pteridinyl.

[0118] In some embodiments, R3and X are taken together with their intervening atoms to form a heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain instances, R3and X are taken together with their intervening atoms to form an optionally substituted triazolyl ring. In some instances, R3 is an optionally substituted C(l-6) aliphatic. In some embodiments, R3 is substituted. In some embodiments, R3 is unsubstituted. In certain embodiments, R3 is C(l-6) alkyl. In certain embodiments, R3 is C(l-4) alkyl. In certain embodiments, R3 is methyl, ethyl, propyl, or isopropyl.

[0119] In some embodiments, X is oxygen or sulfur, or R3 and X are taken together with their intervening atoms to form an optionally substituted 5 -membered heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, X is oxygen. In some embodiments, X is sulfur. In some embodiments, R3 and X are taken together with their intervening atoms to form an optionally substituted 5 -membered heteroaryl ring having 1-4 heteroatomsWSGR Docket No. 65514-707.601independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3 and X are taken together with their intervening atoms to form a substituted 5 -membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3 and X are taken together with their intervening atoms to form an unsubstituted 5 -membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, R3 and X are taken together with their intervening atoms to form an optionally substituted 5 -membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, R3 and X are taken together with their intervening atoms to form an optionally substituted pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, or oxadiazolyl ring.

[0120] In some embodiments, R4is -R, halogen, -OR, -SR, -N(R’)2, -CN, -NO2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, or -OC(O)N(R’)2, where R and R' are as defined and described herein. In some embodiments, R4is -R. In certain embodiments, R4is hydrogen. In certain other embodiments, R4is halogen. In some embodiments, R4is -OR, -SR, or -N(R')2- In certain instances, R4is -OR. In certain instances, R4is -CN or -NO2. In certain instances, R4is -C(O)R, -CO2R, -C(O)N(R')2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')2, or -C(S)OR. In certain instances, R4is -S(O)R, -SO2R, or -SO2N(R')2. In certain instances, R4is -N(R')C(O)R, -N(R')C(O)N(R')2, -N(R')SO2R, -N(R')SO2N(R')2, -N(R')N(R')2, or -N(R')C(=N(R'))N(R')2. In certain instances, R4is -C=NN(R')2, -C=NOR, -C(=N(R'))N(R')2. In certain instances, R4is -OC(O)R or -OC(O)N(R')2.

[0121] In some embodiment m is an integer from 0 to 5. In some instances, m is 1. In some instances, m is 2. In some instances, m is 3. In some instances, m is 4. In certain instances, m is 5.

[0122] In some embodiments, R5is -R, halogen, -OR, -SR, -N(R’)2, -CN, -NO2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, or -OC(O)N(R’)2, where R and R' are as defined and described herein. In some embodiments, R5is -R. In certain embodiments, R5is hydrogen. In certain other embodiments, R5is halogen. In some embodiments, R4is -OR, -SR, or -N(R')2- In certain embodiments, R5is -OR. In other embodiments, R5is -CN or -NO2. In some embodiments, R5is -C(O)R, -CO2R, -C(O)N(R')2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')2, or -C(S)OR. In other embodiments, R5is -S(O)R, -SO2R, or -SO2N(R')2. In certain embodiments, R5is -N(R')C(O)R, -N(R')C(O)N(R')2, -N(R')SO2R, -N(R')SO2N(R')2, -N(R')N(R')2, or -N(R')C(=N(R'))N(R')2. In certain other embodiments, R5is -C=NN(R')2, -C=NOR, -C(=N(R'))N(R')2. In yet other embodiments, R5is -OC(O)R or -OC(O)N(R')2.

[0123] In some embodiment p is an integer from 0 to 5. In some instances, p is 1. In some instances, p is 2. In some instances, p is 3. In some instances, p is 4. In some instances, p is 5.WSGR Docket No. 65514-707.601

[0124] In some embodiments, Y is a covalent bond. In some instances, Y is an optionally substituted bivalent C(l-6) hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In some instances, Y is an optionally substituted bivalent C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NR1-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In certain embodiments, Y is a Ci-3 hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-.

[0125] In some embodiments, each Ri is independently selected from hydrogen, halogen, optionally substituted C(l-6) aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R')2, -N(R’)C(O)R, -N(R’)C(O)N(R')2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)S02N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2, or -(CH2)qRxwherein q is 0-3 and Rxis halogen, optionally substituted C(l-6) aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)Ror -OC(O)N(R’)2. In some embodiments, each Ri is independently selected from hydrogen and a C(l-6) alkyl. In some instances, each Ri is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, each Ri is independently selected from C(l-6) aliphatic, -OR, -N(R’)2, -C(O)R, -OC(O)R, -N(R’)C(O)R, -C(O)NR’, or -CO2R.

[0126] In some embodiments, each R2is independently selected from hydrogen, halogen, optionally substituted C(l-6) aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R')2, -N(R’)C(O)R, -N(R’)C(O)N(R')2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)S02N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2, or -(CH2)qRxwherein q is 0-3 and Rxis halogen, optionally substituted C(l-6) aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)Ror -OC(O)N(R’)2. In some embodiments, each R2is independently selected from hydrogen and a C(l-6) alkyl. In some instances, each R2is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, each R2is independently selected from C(l-6) aliphatic, -OR, -N(R’)2, -C(O)R, -OC(O)R, -N(R’)C(O)R, -C(O)NR’, or -CO2R.

[0127] In some embodiments, n is an integer from Oto 12. In some instances, n is 1. In some instances, n is 2. In some instances, n is 3. In some instances, n is 4. In some instances, n is 5. In some instances, n is 6.

[0128] In some embodiments, Z is -CH2. In some instances, Z is -NH. In some instances, Z is -O-. In some instances, Z is -S-.WSGR Docket No. 65514-707.601

[0129] In some embodiments, the bromodomain- containing 4 ligand is of formula IA1:where:Xi is from C, N, O or S;X2 is from C, N, O or S;X3 is C or N;- represents a single or double bond; andRe is hydrogen, halogen, hydroxyl, alkoxyl, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxy carbonyl, substituted alkoxy carbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, thiol, substituted thiol, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfoximine or substituted sulfoximine.

[0130] In some instances, XI is N or O; X2 is N; and X3 is C or N. In some instances, Xi is N; X2 is N; and X3 is N. In some instances, Xi is O; X2 is N; and X3 is C.

[0131] In some instances, Re is hydrogen or a C(l-6) alkyl. In some instances, Re is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, Re is methyl.

[0132] In some embodiments, n is an integer from 0 to 4. In some instances, n is 1. In some instances, n is 2. In some instances, n is 3. In some instances, n is 4. In some instances, n is 5. In some instances, n is 6.

[0133] In some embodiments, each Ri is independently selected from hydrogen and a C(l-6) alkyl. In some instances, each Ri is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In certain instances, each Ri is independently selected from C(l-6) aliphatic, -OR, -N(R')2, -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR', or -CO2R. In some instances, each Ri is hydrogen or a C(l-6) alkyl. In some instances, each Ri is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, each Ri is methyl.

[0134] In some embodiments, each R2is independently selected from hydrogen and a C(l-6) alkyl. In some instances, each R2 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In certain instances, each R2 is independently selected from C(l-6) aliphatic, -OR, -N(R')2, -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR', or -CO2R. In some instances, each R2 is hydrogen or a C(l-6) alkyl. In some instances, each R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, each R2 is methyl.

[0135] In certain embodiments, n is an integer from 1-4; and each of Ri and R2 are independently selected from hydrogen and a C(l-6) alkyl. In certain instances, n is an integer from 1 -4 and each of RiWSGR Docket No. 65514-707.601and R2 are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, n is an integer from 1 -4 and each of Ri and R2 are methyl. In certain instances, nis i and each of Ri and R2 are hydrogen. In certain instances, n is 1 and each of Ri and R2 are methyl.

[0136] In some embodiments, A is a 5-membered fused heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, A is a 5 -membered fused heteroaryl ring having 2 heteroatoms independently selected from nitrogen or oxygen. In some instances, A is a 5-membered fused heteroaryl ring having 2 heteroatoms selected from nitrogen and oxygen. In some instances, A is a 5- membered fused heteroaryl ring having 2 heteroatoms independently selected from nitrogen or sulfur. In some instances, A is a 5 -membered fused heteroaryl ring having 2 heteroatoms selected from nitrogen and sulfur. In certain instances, A is selected from thiazolo, isothiazolo, oxazolo, isoxazolo, pyrazolo, and imidazolo rings. In certain instances, A is isothiazolo.

[0137] In some embodiments, A is benzo, or a 5-6 membered fused heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, A is a 5-membered fused heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 6-membered fused heteroaryl ring having 2-3 nitrogen atoms. In some instances, A is benzo. In some embodiments, A is a 5-6 membered fused heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, A is a 6-membered fused heteroaryl ring having 1 -3 nitrogen atoms. In certain instance, A is selected from pyrido, pyrimidino, pyrazino, pyridazino, andtriazino, rings. In certain instances, A is a 5 -membered fused heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, or sulfur. In certain instances, A is thieno. In certain instances, A is furano. In certain instances, A is pyrrolo.

[0138] In some embodiments, B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is phenyl. In some instances, B is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In certain instances, B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In certain instances, B is cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0139] In some embodiments, B is a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring B is a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring B is tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, pyrrolidonyl,WSGR Docket No. 65514-707.601piperidinyl, pyrrolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, or morpholinyl.

[0140] In some embodiments, B is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is 6-membered heteroaryl ring having 1-3 nitrogen atoms. In some instances, B is a 6-membered heteroaryl ring having 1 nitrogen atom. In some instances, B is a 6-membered heteroaryl ring having 2 nitrogen atoms. In some instances, B is a 6-membered heteroaryl ring having 3 nitrogen atoms.

[0141] In some embodiments, B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, B is a 5 -membered heteroaryl ring having 1 heteroatom independently selected from nitrogen, oxygen, or sulfur. In some instances, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen and oxygen. In some instances, B is a 5 -membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen and sulfur. In some instances, B is a 5 -membered heteroaryl ring having 1-3 nitrogen atoms. In certain instances, B is selected from thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0142] In some embodiments, B is a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 5,5-fused-, 5,6-fused, or 6,6-fused saturated, partially unsaturated, or aromatic bicyclic ring. In some instances, B is a 5,5-fused, 5,6-fused, or 6,6-fused aromatic bicyclic ring. In some instances, B is a naphthalenyl, indanyl or indenyl group.

[0143] In some embodiments, B is a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 7-8 membered bicyclic saturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 7-8 membered bicyclic partially unsaturated heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 9-10 membered bicyclic saturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instance^ B is a 9-10 membered bicyclic partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, or quinuclidinyl. In some instances, B is selected from indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, 2-azabicyclo[2.2. l]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.

[0144] In some embodiments, B is a 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 5,5-fused, 5,6-fused, or 6,6-fused saturated, partially unsaturated, or aromatic bicyclic ring having 1-4 heteroatoms,WSGR Docket No. 65514-707.601independently selected from nitrogen, oxygen, or sulfur. In some instances, B is a 5,5 -fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur. In certain instances, B is a 5, 5 -fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1-4 nitrogen atoms. In certain instances, B is a 5,6-fused heteroaryl ring having 1-4 nitrogen atoms. In certain instances, B is pyrrolizinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, imidazopyridinyl, indazolyl, purinyl, cinnolinyl, quinazolinyl, phthalazinyl, naphthridinyl, quinoxalinyl, thianaphtheneyl, or benzofuranyl. In certain instances, B is selected from an indolizinyl, purinyl, naphthyridinyl, or pteridinyl.

[0145] In some embodiments, R4is -R, halogen, -OR, -SR, -N(R’)2, -CN, -NO2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, or -OC(O)N(R’)2, where R and R' are as defined and described herein. In some embodiments, R4is -R. In certain embodiments, R4is hydrogen. In certain other embodiments, R4is halogen. In some embodiments, R4is -OR, -SR, or -N(R')2- In certain instances, R4is -OR. In certain instances, R4is -CN or -NO2. In certain instances, R4is -C(O)R, -CO2R, -C(O)N(R')2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')2, or -C(S)OR. In certain instances, R4is -S(O)R, -SO2R, or -SO2N(R')2. In certain instances, R4is -N(R')C(O)R, -N(R')C(O)N(R')2, -N(R')SO2R, -N(R')SO2N(R')2, -N(R')N(R')2, or -N(R')C(=N(R'))N(R')2. In certain instances, R4is -C=NN(R')2, -C=NOR, -C(=N(R'))N(R')2. In certain instances, R4is -OC(O)R or -OC(O)N(R')2.

[0146] In some embodiment m is an integer from 0 to 5. In some instances, m is 1. In some instances, m is 2. In some instances, m is 3. In some instances, m is 4. In certain instances, m is 5.

[0147] In some embodiments, R5is -R, halogen, -OR, -SR, -N(R’)2, -CN, -NO2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, or -OC(O)N(R’)2, where R and R' are as defined and described herein. In some embodiments, R5is -R. In certain embodiments, R5is hydrogen. In certain other embodiments, R5is halogen. In some embodiments, R4is -OR, -SR, or -N(R')2- In certain embodiments, R5is -OR. In other embodiments, R5is -CN or -NO2. In some embodiments, R5is -C(O)R, -CO2R, -C(O)N(R')2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')2, or -C(S)OR. In other embodiments, R5is -S(O)R, -SO2R, or -SO2N(R')2. In certain embodiments, R5is -N(R')C(O)R, -N(R')C(O)N(R')2, -N(R')SO2R, -N(R')SO2N(R')2, -N(R')N(R')2, or -N(R')C(=N(R'))N(R')2. In certain other embodiments, R5is -C=NN(R')2, -C=NOR, -C(=N(R'))N(R')2. In yet other embodiments, R5is -OC(O)R or -OC(O)N(R')2.

[0148] In some embodiment p is an integer from 0 to 5. In some instances, p is 1. In some instances, p is 2. In some instances, p is 3. In some instances, p is 4. In some instances, p is 5.

[0149] In some embodiments, Y is a covalent bond. In some instances, Y is an optionally substituted bivalent C(l-6) hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR'-, -WSGR Docket No. 65514-707.601N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -0-, -C(0)-, -0C(0)-, -C(0)0-, -S-, -SO- or -SO2-. In some instances, Y is an optionally substituted bivalent C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NR1-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In certain embodiments, Y is a Ci-3 hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-.

[0150] In some embodiments, each Ri is independently selected from hydrogen, halogen, optionally substituted C(l-6) aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R')2, -N(R’)C(O)R, -N(R’)C(O)N(R')2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)S02N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2, or -(CH2)qRxwherein q is 0-3 and Rxis halogen, optionally substituted C(l-6) aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)Ror -OC(O)N(R’)2. In some embodiments, each Ri is independently selected from hydrogen and a C(l-6) alkyl. In some instances, each Ri is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, each Ri is independently selected from C(l-6) aliphatic, -OR, -N(R’)2, -C(O)R, -OC(O)R, -N(R’)C(O)R, -C(O)NR’, or -CO2R.

[0151] In some embodiments, each R2is independently selected from hydrogen, halogen, optionally substituted C(l-6) aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R')2, -N(R’)C(O)R, -N(R’)C(O)N(R')2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)S02N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2, or -(CH2)qRxwherein q is 0-3 and Rxis halogen, optionally substituted C(l-6) aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)Ror -OC(O)N(R’)2. In some embodiments, each R2is independently selected from hydrogen and a C(l-6) alkyl. In some instances, each R2is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, each R2is independently selected from C(l-6) aliphatic, -OR, -N(R’)2, -C(O)R, -OC(O)R, -N(R’)C(O)R, -C(O)NR’, or -CO2R.

[0152] In some embodiments, n is an integer from Oto 12. In some instances, n is 1. In some instances, n is 2. In some instances, n is 3. In some instances, n is 4. In some instances, n is 5. In some instances, n is 6.

[0153] In some embodiments, Z is -CH2. In some instances, Z is -NH. In some instances, Z is -O-. In some instances, Z is -S-.

[0154] In some embodiments, the bromodomain- containing 4 ligand (BR) is of formula IA2:WSGR Docket No. 65514-707.601where:Xi is from C, N, O or S;X2 is from C, N, O or S;X3 is C or N;X4 is from CH2, NH, O or S;- represents a single or double bond; andeach of Re, R7 and Rs is independently selected from hydrogen, halogen, hydroxyl, alkoxyl, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxy carbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, thiol, substituted thiol, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfoximine or substituted sulfoximine.

[0155] In some embodiments, X4 is S. In certain instances, - represents a double bond. In some embodiments, Xi is N or O; X2 is N; and X3 is C or N. In some embodiments, Xi is N; X2 is N; and X3 is N.

[0156] In some instances, Re is hydrogen or a C(l-6) alkyl. In some instances, Re is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, Re is methyl. In some instances, R7 is hydrogen or a C(l-6) alkyl. In some instances, R7 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R7 is methyl. In some instances, Rs is hydrogen or a C(l-6) alkyl. In some instances, Rs is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, Rs is methyl. In certain instances, each of Re, R7 and Rs is methyl.

[0157] In some embodiments, B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is phenyl. In some instances, B is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In certain instances, B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In certain instances, B is cyclopentenyl, cyclohexenyl, or cycloheptenyl.WSGR Docket No. 65514-707.601

[0158] In some embodiments, B is a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring B is a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring B is tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, or morpholinyl.

[0159] In some embodiments, B is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is 6-membered heteroaryl ring having 1-3 nitrogen atoms. In some instances, B is a 6-membered heteroaryl ring having 1 nitrogen atom. In some instances, B is a 6-membered heteroaryl ring having 2 nitrogen atoms. In some instances, B is a 6-membered heteroaryl ring having 3 nitrogen atoms.

[0160] In some embodiments, B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, B is a 5 -membered heteroaryl ring having 1 heteroatom independently selected from nitrogen, oxygen, or sulfur. In some instances, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen and oxygen. In some instances, B is a 5 -membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen and sulfur. In some instances, B is a 5 -membered heteroaryl ring having 1-3 nitrogen atoms. In certain instances, B is selected from thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0161] In some embodiments, B is a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 5,5-fused-, 5,6-fused, or 6,6-fused saturated, partially unsaturated, or aromatic bicyclic ring. In some instances, B is a 5,5-fused, 5,6-fused, or 6,6-fused aromatic bicyclic ring. In some instances, B is a naphthalenyl, indanyl or indenyl group.

[0162] In some embodiments, B is a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 7-8 membered bicyclic saturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 7-8 membered bicyclic partially unsaturated heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 9-10 membered bicyclic saturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instance^ B is a 9-10 membered bicyclic partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, or quinuclidinyl. In some instances, B is selected fromWSGR Docket No. 65514-707.601indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, 2-azabicyclo[2.2. l]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.

[0163] In some embodiments, B is a 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 5,5 -fused, 5,6-fused, or 6,6-fused saturated, partially unsaturated, or aromatic bicyclic ring having 1-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur. In some instances, B is a 5,5 -fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur. In certain instances, B is a 5,5-fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1-4 nitrogen atoms. In certain instances, B is a 5,6-fused heteroaryl ring having 1-4 nitrogen atoms. In certain instances, B is pyrrolizinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, imidazopyridinyl, indazolyl, purinyl, cinnolinyl, quinazolinyl, phthalazinyl, naphthridinyl, quinoxalinyl, thianaphtheneyl, or benzofuranyl. In certain instances, B is selected from an indolizinyl, purinyl, naphthyridinyl, or pteridinyl.

[0164] In some embodiments, R5is -R, halogen, -OR, -SR, -N(R’)2, -CN, -NO2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, or -OC(O)N(R’)2, where R and R' are as defined and described herein. In some embodiments, R5is -R. In certain embodiments, R5is hydrogen. In certain other embodiments, R5is halogen. In some embodiments, R4is -OR, -SR, or -N(R')2- In certain embodiments, R5is -OR. In other embodiments, R5is -CN or -NO2. In some embodiments, R5is -C(O)R, -CO2R, -C(O)N(R')2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')2, or -C(S)OR. In other embodiments, R5is -S(O)R, -SO2R, or -SO2N(R')2. In certain embodiments, R5is -N(R')C(O)R, -N(R')C(O)N(R')2, -N(R')SO2R, -N(R')SO2N(R')2, -N(R')N(R')2, or -N(R')C(=N(R'))N(R')2. In certain other embodiments, R5is -C=NN(R')2, -C=NOR, -C(=N(R'))N(R')2. In yet other embodiments, R5is -OC(O)R or -OC(O)N(R')2.

[0165] In some embodiment p is an integer from 0 to 5. In some instances, p is 1. In some instances, p is 2. In some instances, p is 3. In some instances, p is 4. In some instances, p is 5.

[0166] In some embodiments, Y is a covalent bond. In some instances, Y is an optionally substituted bivalent C(l-6) hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In some instances, Y is an optionally substituted bivalent C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NR1-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In certain embodiments, Y is a Ci-3 hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-.

[0167] In some embodiments, each Ri is independently selected from hydrogen, halogen, optionally substituted C(l-6) aliphatic, -OR, -SR, -CN, -N(R’>2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R')2, -N(R’)C(O)R, -N(R’)C(O)N(R')2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)S02N(R’)2, -N(R’)N(R’)2, -WSGR Docket No. 65514-707.601N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -0C(0)N(R’)2, or -(CH2)qRxwherein q is 0-3 and Rxis halogen, optionally substituted C(l-6) aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)Ror -OC(O)N(R’)2. In some embodiments, each Ri is independently selected from hydrogen and a C(l-6) alkyl. In some instances, each Ri is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, each Ri is independently selected from C(l-6) aliphatic, -OR, -N(R')2, -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR', or -CO2R.

[0168] In some embodiments, each R2 is independently selected from hydrogen, halogen, optionally substituted C(l-6) aliphatic, -OR, -SR, -CN, -N(R’>2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R')2, -N(R’)C(O)R, -N(R’)C(O)N(R')2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)S02N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2, or -(CH2)qRxwherein q is 0-3 and Rxis halogen, optionally substituted C(l-6) aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)Ror -OC(O)N(R’)2. In some embodiments, each R2 is independently selected from hydrogen and a C(l-6) alkyl. In some instances, each R2 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, each R2 is independently selected from C(l-6) aliphatic, -OR, -N(R')2, -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR', or -CO2R.

[0169] In some embodiments, n is an integer from Oto 12. In some instances, n is 1. In some instances, n is 2. In some instances, n is 3. In some instances, n is 4. In some instances, n is 5. In some instances, n is 6.

[0170] In some embodiments, Z is -CH2. In some instances, Z is -NH. In some instances, Z is -O-. In some instances, Z is -S-.

[0171] In some embodiments, the bromodomain- containing 4 ligand is of formula IA3:wherein:Xi is from C, N, O or S;WSGR Docket No. 65514-707.601X2 is from C, N, O or S;X3 is C or N;- represents a single or double bond; andeach of Re, R7, Rs, R9 and Rio is independently selected from hydrogen, halogen, hydroxyl, alkoxyl, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxy carbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, thiol, substituted thiol, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfoximine or substituted sulfoxi mine.

[0172] In some instances, Xi is N or O; X2 is N; and X3 is C or N. In some instances, Xi is N; X2 is N; and X3 is N. In some instances, Xi is O; X2 is N; and X3 is C.

[0173] In some instances, Re is hydrogen or a C(l-6) alkyl. In some instances, Re is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, Re is methyl. In some instances, R7 is hydrogen or a C(l-6) alkyl. In some instances, R7 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R7 is hydrogen. In some instances, Rs is hydrogen or a C(l-6) alkyl. In some instances, Rs is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, Rs is hydrogen. In some instances, R9 is hydrogen or a C(l-6) alkyl. In some instances, R9 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R9 is hydrogen. In some instances, Rio is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, Rio is hydrogen. In certain instances, Re is methyl and each of R7, Rs R9 and Rio is hydrogen.

[0174] In some instances, CRe X2 represents a double bond; and CX3 Xi represents a single bond.

[0175] In some embodiments, B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is phenyl. In some instances, B is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In certain instances, B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In certain instances, B is cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0176] In some embodiments, B is a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring B is a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring B isWSGR Docket No. 65514-707.601tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrohdinyl, pyrrohdonyl, piperidinyl, pyrrolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, or morpholinyl.

[0177] In some embodiments, B is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is 6-membered heteroaryl ring having 1-3 nitrogen atoms. In some instances, B is a 6-membered heteroaryl ring having 1 nitrogen atom. In some instances, B is a 6-membered heteroaryl ring having 2 nitrogen atoms. In some instances, B is a 6-membered heteroaryl ring having 3 nitrogen atoms.

[0178] In some embodiments, B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, B is a 5 -membered heteroaryl ring having 1 heteroatom independently selected from nitrogen, oxygen, or sulfur. In some instances, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen and oxygen. In some instances, B is a 5 -membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen and sulfur. In some instances, B is a 5 -membered heteroaryl ring having 1-3 nitrogen atoms. In certain instances, B is selected from thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0179] In some embodiments, B is a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 5,5-fused-, 5,6-fused, or 6,6-fused saturated, partially unsaturated, or aromatic bicyclic ring. In some instances, B is a 5,5-fused, 5,6-fused, or 6,6-fused aromatic bicyclic ring. In some instances, B is a naphthalenyl, indanyl or indenyl group.

[0180] In some embodiments, B is a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 7-8 membered bicyclic saturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 7-8 membered bicyclic partially unsaturated heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 9-10 membered bicyclic saturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instance^ B is a 9-10 membered bicyclic partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, or quinuclidinyl. In some instances, B is selected from indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, 2-azabicyclo[2.2. l]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.

[0181] In some embodiments, B is a 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some instances, B is a 5,5-fused, 5,6-fused,WSGR Docket No. 65514-707.601or 6,6-fused saturated, partially unsaturated, or aromatic bicyclic ring having 1-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur. In some instances, B is a 5,5 -fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur. In certain instances, B is a 5,5-fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1-4 nitrogen atoms. In certain instances, B is a 5,6-fused heteroaryl ring having 1-4 nitrogen atoms. In certain instances, B is pyrrolizinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, imidazopyridinyl, indazolyl, purinyl, cinnolinyl, quinazolinyl, phthalazinyl, naphthridinyl, quinoxalinyl, thianaphtheneyl, or benzofuranyl. In certain instances, B is selected from an indolizinyl, purinyl, naphthyridinyl, or pteridinyl.

[0182] In some embodiments, R5is -R, halogen, -OR, -SR, -N(R’)2, -CN, -NO2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, or -OC(O)N(R’)2, where R and R' are as defined and described herein. In some embodiments, R5is -R. In certain embodiments, R5is hydrogen. In certain other embodiments, R5is halogen. In some embodiments, R4is -OR, -SR, or -N(R')2- In certain embodiments, R5is -OR. In other embodiments, R5is -CN or -NO2. In some embodiments, R5is -C(O)R, -CO2R, -C(O)N(R')2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')2, or -C(S)OR. In other embodiments, R5is -S(O)R, -SO2R, or -SO2N(R')2. In certain embodiments, R5is -N(R')C(O)R, -N(R')C(O)N(R')2, -N(R')SO2R, -N(R')SO2N(R')2, -N(R')N(R')2, or -N(R')C(=N(R'))N(R')2. In certain other embodiments, R5is -C=NN(R')2, -C=NOR, -C(=N(R'))N(R')2. In yet other embodiments, R5is -OC(O)R or -OC(O)N(R')2.

[0183] In some embodiment p is an integer from 0 to 5. In some instances, p is 1. In some instances, p is 2. In some instances, p is 3. In some instances, p is 4. In some instances, p is 5.

[0184] In some embodiments, Y is a covalent bond. In some instances, Y is an optionally substituted bivalent C(l-6) hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In some instances, Y is an optionally substituted bivalent C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NR1-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In certain embodiments, Y is a Ci-3 hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-.

[0185] In some embodiments, each Ri is independently selected from hydrogen, halogen, optionally substituted C(l-6) aliphatic, -OR, -SR, -CN, -N(R’>2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R')2, -N(R’)C(O)R, -N(R’)C(O)N(R')2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)S02N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2, or -(CH2)qRxwherein q is 0-3 and Rxis halogen, optionally substituted C(l-6) aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, -WSGR Docket No. 65514-707.601N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)Ror -OC(O)N(R’)2. In some embodiments, each Ri is independently selected from hydrogen and a C(l-6) alkyl. In some instances, each Ri is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, each Ri is independently selected from C(l-6) aliphatic, -OR, -N(R')2, -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR', or -CO2R.

[0186] In some embodiments, each R2is independently selected from hydrogen, halogen, optionally substituted C(l-6) aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R')2, -N(R’)C(O)R, -N(R’)C(O)N(R')2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)S02N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2, or -(CH2)qRxwherein q is 0-3 and Rxis halogen, optionally substituted C(l-6) aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)Ror -OC(O)N(R’)2. In some embodiments, each R2is independently selected from hydrogen and a C(l-6) alkyl. In some instances, each R2is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, each R2is independently selected from C(l-6) aliphatic, -OR, -N(R’)2, -C(O)R, -OC(O)R, -N(R’)C(O)R, -C(O)NR’, or -CO2R.

[0187] In some embodiments, n is an integer from Oto 12. In some instances, n is 1. In some instances, n is 2. In some instances, n is 3. In some instances, n is 4. In some instances, n is 5. In some instances, n is 6.

[0188] In some embodiments, Z is -CH2. In some instances, Z is -NH. In some instances, Z is -O-. In some instances, Z is -S-.

[0189] In some embodiments, the bromodomain- containing 4 ligand is of formula IA4:where:n is an integer from 0 to 12;m is an integer from 0 to 5;Xi is from C, N, O or S;X2is from C, N, O or S;X3 is C or N;represents a single or double bond;WSGR Docket No. 65514-707.601represents a bond to the linker; andeach of Ri, R2, R4, Re, Rn, R12, R13, R14 and R15 is independently selected from hydrogen, halogen, hydroxyl, alkoxyl, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, thiol, substituted thiol, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfoximine or substituted sulfoximine.

[0190] In some instances, Xi is N or O; X2 is N; and X3 is C or N. In some instances, Xi is N; X2 is N; and X3 is N. In some instances, Xi is O; X2 is N; and X3 is C.

[0191] In some instances, Re is hydrogen or a C(l-6) alkyl. In some instances, Re is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, Re is methyl.

[0192] In some instances, Rn is selected from hydrogen, halogen or a C(l-6) alkyl. In some instances, R11 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, Rn is hydrogen. In some instances, R12 is selected from hydrogen, halogen or a C(l-6) alkyl. In some instances, R12 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R12 is hydrogen. In some instances, R13 is selected from hydrogen, halogen or a C(l-6) alkyl. In some instances, R13 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R13 is hydrogen. In certain instances, R13 is halogen. In certain instances, R13 is selected from fluorine, chlorine, bromine and iodine. In certain instances, R13 is chlorine. In some instances, R14 is selected from hydrogen, halogen or a C(l-6) alkyl. In some instances, R14 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R14 is hydrogen. In some instances, R15 is selected from hydrogen, halogen or a C(l-6) alkyl. In some instances, R15 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R15 is hydrogen. In certain embodiments, each one of Rn, R12, R14 and R15 is hydrogen and R13 is selected from fluorine, chlorine, bromine and iodine. In certain embodiments, each one of Rn, R12, R14 and R15 is hydrogen and R13 is chlorine.

[0193] In some embodiments, A is a 5-membered fused heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, A is a 5 -membered fused heteroaryl ring having 2 heteroatoms independently selected from nitrogen or oxygen. In some instances, A is a 5-membered fused heteroaryl ring having 2 heteroatoms selected from nitrogen and oxygen. In some instances, A is a 5- membered fused heteroaryl ring having 2 heteroatoms independently selected from nitrogen or sulfur. In some instances, A is a 5 -membered fused heteroaryl ring having 2 heteroatoms selected from nitrogen and sulfur. In certain instances, A is selected from thiazolo, isothiazolo, oxazolo, isoxazolo, pyrazolo, and imidazolo rings. In certain instances, A is isothiazolo.

[0194] In some embodiments, A is benzo, or a 5-6 membered fused heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, A is a 5-membered fused heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 6-membered fused heteroaryl ring having 2-3 nitrogen atoms. In some instances, A isWSGR Docket No. 65514-707.601benzo. In some embodiments, A is a 5-6 membered fused heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some instances, A is a 6 -membered fused heteroaryl ring having 1-3 nitrogen atoms. In certain instance, A is selected from pyrido, pyrimidino, pyrazino, pyridazino, andtriazino, rings. In certain instances, A is a 5 -membered fused heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, or sulfur. In certain instances, A is thieno. In certain instances, A is furano. In certain instances, A is pyrrolo.

[0195] In some embodiments, R4is -R, halogen, -OR, -SR, -N(R’)2, -CN, -NO2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, or -OC(O)N(R’)2, where R and R' are as defined and described herein. In some embodiments, R4is -R. In certain embodiments, R4is hydrogen. In certain other embodiments, R4is halogen. In some embodiments, R4is -OR, -SR, or -N(R')2- In certain instances, R4is -OR. In certain instances, R4is -CN or -NO2. In certain instances, R4is -C(O)R, -CO2R, -C(O)N(R')2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')2, or -C(S)OR. In certain instances, R4is -S(O)R, -SO2R, or -SO2N(R')2. In certain instances, R4is -N(R')C(O)R, -N(R')C(O)N(R')2, -N(R')SO2R, -N(R')SO2N(R')2, -N(R')N(R')2, or -N(R')C(=N(R'))N(R')2. In certain instances, R4is -C=NN(R')2, -C=NOR, -C(=N(R'))N(R')2. In certain instances, R4is -OC(O)R or -OC(O)N(R')2.

[0196] In some embodiment m is an integer from 0 to 5. In some instances, m is 1. In some instances, m is 2. In some instances, m is 3. In some instances, m is 4. In certain instances, m is 5.

[0197] In some embodiments, each Ri is independently selected from hydrogen and a C(l-6) alkyl. In some instances, each Ri is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In certain instances, each Ri is independently selected from C(l-6) aliphatic, -OR, -N(R')2, -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR', or -CO2R. In some instances, each Ri is hydrogen or a C(l-6) alkyl. In some instances, each Ri is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, each Ri is methyl.

[0198] In some embodiments, each R2is independently selected from hydrogen and a C(l-6) alkyl. In some instances, each R2 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In certain instances, each R2 is independently selected from C(l-6) aliphatic, -OR, -N(R')2, -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR', or -CO2R. In some instances, each R2 is hydrogen or a C(l-6) alkyl. In some instances, each R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, each R2 is methyl.

[0199] In certain embodiments, n is an integer from 1-4; and each of Ri and R2 are independently selected from hydrogen and a C(l-6) alkyl. In certain instances, n is an integer from 1 -4 and each of Ri and R2 are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, n is an integer from 1 -4 and each of Ri and R2 are methyl. In certain instances, nis i and each of Ri and R2 are hydrogen. In certain instances, n is 1 and each of Ri and R2 are methyl.WSGR Docket No. 65514-707.601

[0200] In some embodiments, Z is -CH2. In some instances, Z is -NH. In some instances, Z is -O-. In some instances, Z is -S-.

[0201] In certain embodiments, the bromodomain- containing 4 ligand is a compound as described in International Patent Publication No. WO2012 / 075456, the disclosure of which is incorporated by reference.

[0202] In certain embodiments, the bromodomain-containing 4 ligand is selected from:where represents a bond to the linker.

[0203] In certain embodiments, the bromodomain-containing 4 ligand is of formula IA5:where 'z r r rkrepresents a bond to the linker.

[0204] In certain embodiments, the bromodomain-containing 4 ligand is selected from:where represents a bond to the linker.

[0205] In certain embodiments, the bromodomain-containing 4 ligand is selected from:WSGR Docket No. 65514-707.601where represents a bond to the linker.

[0206] In certain embodiments, the bromodomain-containing 4 ligand is selected from:WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601

[0207] In some instances, the ligand is JQ1.CDK Ligands o

[0208] Methods of treating a subject for an autoimmune disease or disorder are provided. In some cases, the methods can include administering a CIP which links a BTB domain- containing protein (e.g., BCL6) or the transcriptional repressor expressed in B cell subpopulations (e.g., PRD 6 zM1, IRF4) and Q — y ' / / A -CDK9 to treat the subject for the autoimmune disease or disorder. Also provided are compositions that find use in practicing methods of the disclosure. CM o

[0209] Suitable lig 2 IZ Xands for CDK9 include, but are not limited to, those described in published PCT application Publication Nos.: WO / 2022 / 098843; WO / 2022 / 028556; WO / 2021 / 260578;Q WO / 2021 / 227904; WO / 2021 / 172359; WO / 2020 / 259556; WO / 2 z\ X 020 / 244612; WO / 2020 / 228513;WO / 2020 / 202232; WO / 2020 / 117988; WO / 2020 / 092314; WO / 2019 / 242471; WO / 2019 / 209825;oWO / 2019 / 058348 WO / 2018 / 192273; WO / 2017 / 185023 \; WO / 2017 / 001354; WO / 2016 / 061144;WO / 2015 / 119712; WO / 2014 / 160028; WO / 2014 / 159999; WO / 2014 / 160017; WO / 2014 / 151444;WO / 2014 / 139328; WO / 2013 / 059634; WO / 2013 / 026874; WO / 2012 / 101062; WO / 2012 / 101065;WO / 2007 / 117653; and WO / 2005 / 027902; WO / 2004 / 002226; the disclosures of which are herein incorporated by reference.

[0210] Specific CDK9 ligands of interest include, but are not limited to:Name Reference StructureSNS-032 Nature Chem Biol, 2018, 14, 163-173p-^L<9 flA. TAi HSNVP-2 WO / 2011 / 01266KI -ARv-03 ACS Med. Chem. Lett. 2018, 9, 6,540-545KB-0742 ACS Med. Chem. Lett. 2018, 9, 6,[ )— NH2540-545 HN"LXBAY- ChemMedChem 2017, 12, 1776- f^LihnA A k JL 's''1143572 1793 1 J H °WSGR Docket No. 65514-707.601AZD-4573 Clin Cancer Res 2020, 26, 922-934.N-N--X _i zC ci\ N J-A ON J o.... ■ HAlvocidib Blood Cancer Journal (2021) 11:175P x\ HO.0 '<CiOH O ZT O TP-1287 Cancer Res (2017) 77tJ-—N(13_Supplement): 5133 LLcF" T A HO- '..0... ^..O ''-yZN-F Cl OH ORiviciclib Mol Cancer Ther. 2007 / z-N / \ OH Mar; 6(3): 926-34.HOYYYQ OH OVoruciclib Scientific Reports, 2017, 7, 18007 r— r / CF3ci OH O ZK-304709 Gut 2009;58:261-270 HO H2N. PH,A ■> TQ. N N H BAY- J Enzyme Inhib Med Chem. 2021;1251152 36(1): 693-706.WSGR Docket No. 65514-707.601Zotiraciclib Clin Cancer Res (2021) 27 (12):(TG-02) 3298-3306.0 N N '''HSeliciclib Journal of Biotechnology 202 (2015) OH |40-49 NHw n Fadraciclib Leukemia volume 36, pagesl596- OH j 1608 (2022)NHnHhkXj pO zN. JJ K n / Z xy- Dinaciclib Scientific Reports volume 10, XoIZ / ^zArticle number: 18489 (2020)1 / J\ \ _ 0QX%,]' HN-\fVo- AT7519 Oncogene volume 29, pages2325- 2336 (2010)BTX-A51 Clarivate Analytics Integrity.https: / / integrity. clarivate. comBlood (2020) 136 (Supplement 1):18.WSGR Docket No. 65514-707.601BCL6 ligands

[0211] Any one of the methods of the present disclosure can comprise providing in the cell, e.g., via a protocol such as described below, a CIP which links BCL6 with a modulator of gene regulation (e.g., BRD4, CDK9, p300), wherein CIP mediated linkage of these factors enhances transcription of the proapoptotic gene in the cell. In some instances, CIPs employed in these embodiments are generally as described above and include a first ligand that specifically binds to BCL-6, and a second ligand that specifically binds to a modulator of gene regulation, where these first and second ligands are j oined by a bond or suitable linker, e.g., as described below.

[0212] Suitable BCL6 ligands include, but are not limited to, those described in U. S. Patent Nos. 11,242,351; 11,192,880; 11,161,839; 11,001,570; 9,943,506; 8,791,075; 8,703,503; 8,338,464; and 7,919,578, as well as those described in United States Patent Application Publication Nos. 20210330672; 20210206756; 20210163497; 20210147382; 20210053978; 20200331921; 20200325119; 20200308147; 20200071297; 20160166549; 20120014979; 20100130564; 20090018083; the disclosures of which are herein incorporated by reference.

[0213] In some embodiments, the BCL6 ligand is of formula IB:0(IB)where:D is selected from a bond, alkyl, amide, ester, carbamate, acyl, substituted acyl, carboxyl, alkoxy carbonyl, substituted alkoxy carbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino and substituted acylamino;E is -CH or nitrogen;WSGR Docket No. 65514-707.601G is nitrogen or CR23, wherein R23 is selected from hydrogen, — C(l-4) alkyl, — O — C(l-14) alkyl, — O — C(l-4) haloalkyl, — C(l-4) haloalkyl and halogen;J is -CH or nitrogen;M is -CH or nitrogen;K is -CH2, O, S or -NH;represents a bond to the linker; andeach of Ri6, R17, Ris, R19, R20, R21 R22 is independently selected from hydrogen, halogen, hydroxyl, alkoxyl, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, thiol, substituted thiol, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfoximine or substituted sulfoximine.

[0214] In some instances, D is an amide. In some embodiments, D is an optionally substituted C(l-6) aliphatic. In some embodiments, D is substituted. In some embodiments, D is unsubstituted. In certain embodiments, D is C(l-6) alkyl. In certain embodiments, D is C(l-4) alkyl. In certain embodiments, D is methyl, ethyl, propyl, or isopropyl. In some instances, D is an optionally substituted bivalent C(l-6) hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In some instances, D is an optionally substituted bivalent C(1 -3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In certain embodiments, D is a C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-.

[0215] In certain instances, E is nitrogen. In certain instances, E is -CH.

[0216] In some instances, Ri6 is selected from hydrogen, halogen or a C(l-6) alkyl. In some instances, Ri6 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, Ri6 is hydrogen. In certain instances, Ri6 is halogen. In some instances, Ri6 is selected from fluorine, chlorine, bromine and iodine. In some instances, Ri6 is chlorine.

[0217] In some instances, R17 is selected from hydrogen, halogen or a C(1 -6) alkyl. In some instances, R17 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R17 is hydrogen. In certain instances, R17 is halogen. In some instances, R17 is selected from fluorine, chlorine, bromine and iodine. In some instances, R17 is chlorine. In certain instances, Ri6 is hydrogen and R17 is chlorine.

[0218] In some embodiments, R18 is selected from hydrogen, — C(l-4) alkyl, — O — C(l-4) alkyl and halogen. In some instances, Ris is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In some instances, R18 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy or tert-butoxy. In some instances, R18 is an optionally substituted bivalent C(1 -6) hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SC>2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In some instances, Ris is anWSGR Docket No. 65514-707.601optionally substituted bivalent C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SO2N(R')-. -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In certain embodiments, Ris is a C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-. In some instances, Ris is selected from fluorine, chlorine, bromine and iodine.

[0219] In some instances, R19 is selected from hydrogen, halogen or a C(1 -6) alkyl. In some instances, Rig is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R19 is hydrogen. In certain instances, R19 is halogen. In some instances, R19 is selected from fluorine, chlorine, bromine and iodine. In some instances, R19 is chlorine. In certain instances, Ri6 is hydrogen, R17 is chlorine and R19 is hydrogen.

[0220] In some embodiments, G is CR23 and R23 is selected from hydrogen, C(l-4) alkyl, — O — C(l-4) alkyl, — O — C(l-4) haloalkyl, and halogen. In some instances, R23 is hydrogen, — C(l-4) alkyl, — O — C(l-4) alkyl and halogen. In some instances, R23 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In some instances, R23 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy or tert-butoxy. In some instances, R23 is an optionally substituted bivalent C(l-6) hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In some instances, R23 is an optionally substituted bivalent C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NR1-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or-SO2-. In certain embodiments, R23 is aC(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-. In some instances, R23 is selected from fluorine, chlorine, bromine and iodine.

[0221] In some instances, J is -CH. In some instances, J is nitrogen. In some instances, M is -CH. In some instances, M is nitrogen. In some instances, K is -CH2. In some instances, K is oxygen. In some instances, K is sulfur. In some instances, K is -NH.

[0222] In some embodiments, R21 is selected from hydrogen, — C(l-6) alkyl optionally substituted with one group selected from — OH, — NH2, — O — Ci-4alkyl, — NH — C(l-4) alkyl, — N(Ci-4alkyl)2, — C(3-6) cycloalkyl and 4 to 7 membered heterocyclyl, wherein each cycloalkyl and heterocyclyl group is optionally and independently substituted by one group selected from — C(l-3) alkyl or R21 is — C(3-6) cycloalkyl, 4 to 7 membered heterocyclyl, wherein each group is optionally substituted by one group selected from — C(l-3) alkyl. In some instances, R21 is selected from — C(l-4) alkyl, optionally substituted with one group selected from — OH, — C(3-6) cycloalkyl and — N(Ci-4alkyl)2. In some embodiments, R21 is selected from — CH3, — CH2CH3, — CH2CH2CH3, — 04(043)2, — (CkbROH. — (012)2(043)2, — CH2-cyclopropyl and — (CH2)2N(CH3)2. In some instances, R21 is hydrogen or a C(l-6) alkyl. In some instances, R21 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R21 is methyl.

[0223] In some embodiments, R20 is selected from hydrogen, — C(l-4) alkyl, — O — C(l-4) alkyl and halogen. In certain instances, R20 is hydrogen. In some instances, R20 is selected from methyl, ethyl, n-WSGR Docket No. 65514-707.601propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In some instances, R20 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy or tert-butoxy. In some instances, R20 is an optionally substituted bivalent C(l-6) hydrocarbon chain wherein one or two methylene units is ' o \ Ioptionally O O ''vv' Q r Z —w —eplaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, 0 2 - *vv'SO- or -SO2-. In some instances, R20 is an optionally substituted bivalent C(l-3)HOhydrocarbon chain wherein one methylene unit is optionally replaced by -NR1-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or-SO2-. In certain embodiments, R20 is a C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-. In some instanc Ies, R20 is selected from fluorine, chlorine, bromine and iodine.t O

[0224] In some embodimen s, R22 i Is -LI-C(R24R2S)O — R26 or — CH=CH — R26 wherein Li is — O — O C / JW- or — — / S —; R24 is hydrogen or C(l-4) alkyl; R2s CO ' 'W'is hydrogen or C(l-4) alkyl; or R24and R25 taken together form a — C(3-5) cycloalkyl; R26is— COOH, — r CONH2, — C(O)R27, — C(O)OR27, — C(O)NR27R28, — S(O)— Ci-ealkyl, — S(O)2— C(l-6) alkyl, — P(O) — (Ci-ealkyl)2, — C(NH)NH2, R2?is a 3-6 membered heterocyclyl or — C(l-4) alkyl optionally substituted by one or more, identical or different groups selected from — OH, — CF3, — N(Ci-4alkyl)2, — C(3-6) cycloalkyl, 3-6 membered heterocyclyl, — C(2-4)' z —alkenyl, — C2-4alkynyl; and R.2S is hydO O -AA-r Aogen or C(l-4) alkyl. I 1 IT Q O Q Z 2 C / J-wv-'w'n 'vv* — — certain instances, R22 is selected from:O O'W' - HH t oO^ 0HO^ ND \ I0 0^ / Z \ — IO ' Z'vw’ —HCF ^O HN' X) HN' r O Q 'W'-vu - X)HN' X) HN" X)WSGR Docket No. 65514-707.601© O Q-w / \ f W—© / 0© O O'w* □ J / 'Io© / .HN 0

[0225] In some embodiments, R22 is: I

[0226] In certain embodiments, the BCL6 ligand is of formula IB1:v= O 2 >vv'*—HOQ O — AO O (IB1).

[0227] In certain embodiments, the BCL6 ligand is of formula IB2:Z. —

[0228] In certain embodiments, the BCL6 ligand is of formula IB3:

[0229] In certain embodiments, the BCL6 ligand is of formula IB4:WSGR Docket No. 65514-707.601o o (IB4).

[0230] In certain embodiments, the BCL6 ligand is of formula IB5:where:D is selected from a bond, alkyl, amide, ester, carbamate, acyl, substituted acyl, carboxyl, alkoxy carbonyl, substituted alkoxy carbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino and substituted acylamino;E is -CH or nitrogen;G is nitrogen or CR23, wherein R23 is selected from hydrogen, — C(l-4) alkyl, — O — C(l-14) alkyl, — O — C(l-4) haloalkyl, — C(l-4) haloalkyl and halogen;J is -CH or nitrogen;M is -CH or nitrogen;Q is -CH or nitrogen;K is -CH2, O, S or NH;represents a bond to the linker; andeach of Ri6, R17, Ris, R19, R20 and R21 is independently selected from hydrogen, halogen, hydroxyl, alkoxyl, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, thiol, substituted thiol, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfoximine or substituted sulfoximine.

[0231] In some instances, D is an amide. In some embodiments, D is an optionally substituted C(l-6) aliphatic. In some embodiments, D is substituted. In some embodiments, D is unsubstituted. In certain embodiments, D is C(l-6) alkyl. In certain embodiments, D is C(l-4) alkyl. In certain embodiments, D is methyl, ethyl, propyl, or isopropyl. In some instances, D is an optionally substituted bivalent C(l-6) hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR'-, -N(R')C(O)-, -WSGR Docket No. 65514-707.601C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -0-, -C(0)-, -0C(0)-, -C(0)0-, -S-, -SO- or -SO2-. In some instances, D is an optionally substituted bivalent C(1 -3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In certain embodiments, D is a C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-.

[0232] In certain instances, E is nitrogen. In certain instances, E is -CH.

[0233] In some instances, Ri6 is selected from hydrogen, halogen or a C(l-6) alkyl. In some instances, Ri6 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, Ri6 is hydrogen. In certain instances, Ri6 is halogen. In some instances, Ri6 is selected from fluorine, chlorine, bromine and iodine. In some instances, Ri6 is chlorine.

[0234] In some instances, R17 is selected from hydrogen, halogen or a C(1 -6) alkyl. In some instances, Ri 7 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, Ri? is hydrogen. In certain instances, R17 is halogen. In some instances, R17 is selected from fluorine, chlorine, bromine and iodine. In some instances, R17 is chlorine. In certain instances, Ri6 is hydrogen and R17 is chlorine.

[0235] In some embodiments, Ris is selected from hydrogen, — C(l-4) alkyl, — O — C(l-4) alkyl and halogen. In some instances, Ris is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In some instances, Ris is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy or tert-butoxy. In some instances, Ris is an optionally substituted bivalent C(1 -6) hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In some instances, Ris is an optionally substituted bivalent C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SO2N(R')-. -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In certain embodiments, Ris is a C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-. In some instances, Ris is selected from fluorine, chlorine, bromine and iodine.

[0236] In some instances, R19 is selected from hydrogen, halogen or a C(1 -6) alkyl. In some instances, Rig is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R19 is hydrogen. In certain instances, R19 is halogen. In some instances, R19 is selected from fluorine, chlorine, bromine and iodine. In some instances, R19 is chlorine. In certain instances, Ri6 is hydrogen, R17 is chlorine and R19 is hydrogen.

[0237] In some embodiments, G is CR23 and R23 is selected from hydrogen, C(l-4) alkyl, — O — C(l-4) alkyl, — O — C(l-4) haloalkyl, and halogen. In some instances, R23 is hydrogen, — C(l-4) alkyl, — O — C(l-4) alkyl and halogen. In some instances, R23 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In some instances, R23 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy or tert-butoxy. In some instances, R23 is an optionally substituted bivalent C(l-6) hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. InWSGR Docket No. 65514-707.601some instances, R23 is an optionally substituted bivalent C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SC>2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or-SO2-. In certain embodiments, R23 is aC(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-. In some instances, R23 is selected from fluorine, chlorine, bromine and iodine.

[0238] In some instances, J is -CH. In some instances, J is nitrogen. In some instances, M is -CH. In some instances, M is nitrogen. In some instances, K is -CH2. In some instances, K is oxygen. In some instances, K is sulfur. In some instances, K is -NH.

[0239] In some embodiments, R20 is selected from hydrogen, — C(l-4) alkyl, — O — C(l-4) alkyl and halogen. In certain instances, R20 is hydrogen. In some instances, R20 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In some embodiments, R20 is methyl. In some instances, R20 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy or tertbutoxy. In some instances, R20 is an optionally substituted bivalent C(l-6) hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In some instances, R20 is an optionally substituted bivalent C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In certain embodiments, R20 is a C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-. In some instances, R20 is selected from fluorine, chlorine, bromine and iodine.

[0240] In some embodiments, R21 is selected from hydrogen, — C(l-6) alkyl optionally substituted with one group selected from — OH, — NH2, — O — Ci-4alkyl, — NH — C(l-4) alkyl, — N(Ci-4alkyl)2, — C(3-6) cycloalkyl and 4 to 7 membered heterocyclyl, wherein each cycloalkyl and heterocyclyl group is optionally and independently substituted by one group selected from — C(l-3) alkyl or R21 is — C(3-6) cycloalkyl, 4 to 7 membered heterocyclyl, wherein each group is optionally substituted by one group selected from — C(l-3) alkyl. In some instances, R21 is selected from — C(l-4) alkyl, optionally substituted with one group selected from — OH, — C(3-6) cycloalkyl and — N(Ci-4alkyl)2. In some instances, R21 is selected from — CH3, — CH2CH3, — CH2CH2CH3, — CH(CH3)2, — (CH2)3OH, —(012)2(043)2, — CH2-cyclopropyl and — (Ob^N O^ In certain embodiments, R21 is |nsome instances, R21 is selected from — C(l-4) alkyl, optionally substituted with one group selected from — OH, — C(3-6) cycloalkyl and — N(O-4alkyl)2. In some embodiments, R21 is selected from — CH3, — CH2CH3, — CH2CH2CH3, — CH(CH3)2, — (CH2)3OH, — (012)2(013)2, — CH2-cyclopropyl and — (042)2^043)2. In some instances, R21 is hydrogen or a C(1 -6) alkyl. In some instances, R21 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R21 is methyl.

[0241] In certain embodiments, the BCL6 ligand is of formula IB6:WSGR Docket No. 65514-707.601where represents a bond to the linker.

[0242] In some embodiments, the BCL6 ligand is of formula IB7:o (IB7)where:D is selected from a bond, alkyl, amide, ester, carbamate, acyl, substituted acyl, carboxyl, alkoxy carbonyl, substituted alkoxy carbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino and substituted acylamino;E is -CH or nitrogen;G is nitrogen or CR23, wherein R23 is selected from hydrogen, — C(l-4) alkyl, — O — C(l-14) alkyl, — O — C(l-4) haloalkyl, — C(l-4) haloalkyl and halogen;J is -CH or nitrogen;M is -CH or nitrogen;K is -CH2, O, S or NH;represents a bond to the linker; andeach of Ri6, R17, Ris, R19 and R21 is independently selected from hydrogen, halogen, hydroxyl, alkoxyl, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxy carbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, thiol, substituted thiol, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfoximine or substituted sulfoximine.

[0243] In some instances, D is an amide. In some embodiments, D is an optionally substituted C(l-6) aliphatic. In some embodiments, D is substituted. In some embodiments, D is unsubstituted. In certain embodiments, D is C(l-6) alkyl. In certain embodiments, D is C(l-4) alkyl. In certain embodiments, D is methyl, ethyl, propyl, or isopropyl. In some instances, D is an optionally substituted bivalent C(l-6)WSGR Docket No. 65514-707.601hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In some instances, D is an optionally substituted bivalent C(1 -3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In certain embodiments, D is a C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-.

[0244] In certain instances, E is nitrogen. In certain instances, E is -CH.

[0245] In some instances, Ri6 is selected from hydrogen, halogen or a C(l-6) alkyl. In some instances, Ri6 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, Ri6 is hydrogen. In certain instances, Ri6 is halogen. In some instances, Ri6 is selected from fluorine, chlorine, bromine and iodine. In some instances, Ri6 is chlorine.

[0246] In some instances, R17 is selected from hydrogen, halogen or a C(1 -6) alkyl. In some instances, Ri 7 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, Ri? is hydrogen. In certain instances, R17 is halogen. In some instances, R17 is selected from fluorine, chlorine, bromine and iodine. In some instances, R17 is chlorine. In certain instances, Ri6 is hydrogen and R17 is chlorine.

[0247] In some embodiments, Ris is selected from hydrogen, — C(l-4) alkyl, — O — C(l-4) alkyl and halogen. In some instances, Ris is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In some instances, Ris is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy or tert-butoxy. In some instances, Ris is an optionally substituted bivalent C(1 -6) hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In some instances, Ris is an optionally substituted bivalent C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SO2N(R')-. -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In certain embodiments, Ris is a C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-. In some instances, Ris is selected from fluorine, chlorine, bromine and iodine.

[0248] In some instances, R19 is selected from hydrogen, halogen or a C(1 -6) alkyl. In some instances, Rig is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R19 is hydrogen. In certain instances, R19 is halogen. In some instances, R19 is selected from fluorine, chlorine, bromine and iodine. In some instances, R19 is chlorine. In certain instances, Ri6 is hydrogen, R17 is chlorine and R19 is hydrogen.

[0249] In some embodiments, G is CR23 and R23 is selected from hydrogen, C(l-4) alkyl, — O — C(l-4) alkyl, — O — C(l-4) haloalkyl, and halogen. In some instances, R23 is hydrogen, — C(l-4) alkyl, — O — C(l-4) alkyl and halogen. In some instances, R23 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In some instances, R23 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy or tert-butoxy. In some instances, R23 is an optionally substituted bivalent C(l-6) hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR'-, -WSGR Docket No. 65514-707.601N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -0-, -C(0)-, -0C(0)-, -C(0)0-, -S-, -SO- or -SO2-. In some instances, R23 is an optionally substituted bivalent C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NR1-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or-SO2-. In certain embodiments, R23 is aC(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-. In some instances, R23 is selected from fluorine, chlorine, bromine and iodine.

[0250] In some instances, J is -CH. In some instances, J is nitrogen. In some instances, M is -CH. In some instances, M is nitrogen. In some instances, K is -CH2. In some instances, K is oxygen. In some instances, K is sulfur. In some instances, K is -NH.

[0251] In some embodiments, R2I is selected from hydrogen, — C(l-6) alkyl optionally substituted with one group selected from — OH, — NH2, — O — Ci-4alkyl, — NH — C(l-4) alkyl, — N(Ci-4alkyl)2, — C(3-6) cycloalkyl and 4 to 7 membered heterocyclyl, wherein each cycloalkyl and heterocyclyl group is optionally and independently substituted by one group selected from — C(l-3) alkyl or R2I is — C(3-6) cycloalkyl, 4 to 7 membered heterocyclyl, wherein each group is optionally substituted by one group selected from — C(l-3) alkyl. In some instances, R2I is selected from — C(l-4) alkyl, optionally substituted with one group selected from — OH, — C(3-6) cycloalkyl and — N(Ci-4alkyl)2. In some embodiments, R2I is selected from — CH3, — CH2CH3, — CH2CH2CH3, — CH(CH3)2, — (CH2)3OH, — (CH2)2(CH3)2, — CH2-cyclopropyl and — (CH2)2N(CH3)2. In some instances, R2I is hydrogen or a C(l-6) alkyl. In some instances, R2I is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R2I is methyl.

[0252] In certain embodiments, the BCL6 ligand is of formula IB8:wherein represents a bond to the linker.

[0253] In some embodiments the BCL6 ligand is of formula IB9:where:WSGR Docket No. 65514-707.601D is selected from a bond, alkyl, amide, ester, carbamate, acyl, substituted acyl, carboxyl, alkoxy carbonyl, substituted alkoxy carbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino and substituted acylamino;E is -CH or nitrogen;J is -CH or nitrogen;M is -CH or nitrogen;K is -CH2, O, S or NH;represents a bond to the linker; andeach of Ri6, R17, RIS, R19 and R21 is independently selected from hydrogen, halogen, hydroxyl, alkoxyl, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxy carbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, thiol, substituted thiol, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfoximine or substituted sulfoximine.

[0254] In some instances, D is an amide. In some embodiments, D is an optionally substituted C(l-6) aliphatic. In some embodiments, D is substituted. In some embodiments, D is unsubstituted. In certain embodiments, D is C(l-6) alkyl. In certain embodiments, D is C(l-4) alkyl. In certain embodiments, D is methyl, ethyl, propyl, or isopropyl. In some instances, D is an optionally substituted bivalent C(l-6) hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In some instances, D is an optionally substituted bivalent C(1 -3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In certain embodiments, D is a C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-.

[0255] In certain instances, E is nitrogen. In certain instances, E is -CH.

[0256] In some instances, Ri6 is selected from hydrogen, halogen or a C(l-6) alkyl. In some instances, Ri6 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, Ri6 is hydrogen. In certain instances, Ri6 is halogen. In some instances, Ri6 is selected from fluorine, chlorine, bromine and iodine. In some instances, Ri6 is chlorine.

[0257] In some instances, R17 is selected from hydrogen, halogen or a C(1 -6) alkyl. In some instances, R17 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R17 is hydrogen. In certain instances, R17 is halogen. In some instances, R17 is selected from fluorine, chlorine, bromine and iodine. In some instances, R17 is chlorine. In certain instances, Ri6 is hydrogen and R17 is chlorine.

[0258] In some embodiments, R18 is selected from hydrogen, — C(l-4) alkyl, — O — C(l-4) alkyl and halogen. In some instances, Ris is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In some instances, R18 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy or tert-butoxy. In some instances, R18 is an optionally substituted bivalent C(1 -6) hydrocarbonWSGR Docket No. 65514-707.601chain wherein one or two methylene units is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In some instances, Ris is an optionally substituted bivalent C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')- -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-. In certain embodiments, Ris is a C(l-3) hydrocarbon chain wherein one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)-, or -SO2-. In some instances, Ris is selected from fluorine, chlorine, bromine and iodine.

[0259] In some instances, R19 is selected from hydrogen, halogen or a C(1 -6) alkyl. In some instances, Rig is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R19 is hydrogen. In certain instances, R19 is halogen. In some instances, R19 is selected from fluorine, chlorine, bromine and iodine. In some instances, R19 is chlorine. In certain instances, Ri6 is hydrogen, R17 is chlorine and R19 is hydrogen.

[0260] In some instances, J is -CH. In some instances, J is nitrogen. In some instances, M is -CH. In some instances, M is nitrogen. In some instances, K is -CH2. In some instances, K is oxygen. In some instances, K is sulfur. In some instances, K is -NH.

[0261] In some embodiments, R21 is selected from hydrogen, — C(l-6) alkyl optionally substituted with one group selected from — OH, — NH2, — O — Ci-4alkyl, — NH — C(l-4) alkyl, — N(Ci-4alkyl)2, — C(3-6) cycloalkyl and 4 to 7 membered heterocyclyl, wherein each cycloalkyl and heterocyclyl group is optionally and independently substituted by one group selected from — C(l-3) alkyl or R21 is — C(3-6) cycloalkyl, 4 to 7 membered heterocyclyl, wherein each group is optionally substituted by one group selected from — C(l-3) alkyl. In some instances, R21 is selected from — C(l-4) alkyl, optionally substituted with one group selected from — OH, — C(3-6) cycloalkyl and — N(Ci-4alkyl)2. In some embodiments, R21 is selected from — CH3, — CH2CH3, — CH2CH2CH3, — CH( 013)2, — (CH2)3OH, — (012)2(013)2, — CH2-cyclopropyl and — (CH2)2N(CH3)2. In some instances, R21 is hydrogen or a C(l-6) alkyl. In some instances, R21 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl. In certain instances, R21 is methyl.

[0262] Additional suitable BCL6 ligands may include, but are not limited to:WSGR Docket No. 65514-707.601O HN HN" NH k Cl W.j- < V''N '’V JHtr ' "-OHH11 Cq;,-pa' “' NH f l ( >r " N"253 6 14. N. ^O HN N-^CiI H J!2 I) " N" -N', N: HOII O HO FX1HN', N. 0< H ‘::o NH N 0.V-N 0 O, N A H (BI-3802) (14). ON.. N N,:N H HN.. N N HH' OCl-A N •' 'N V IZV' r O \CMnHN,.?fF(6) (CCT369347) (CCT372064)-Ci,--^N N q H HN / N H F OH(CCT37566) (CCTT369260)WSGR Docket No. 65514-707.601(TMX-2164)f '16(BCI-1) (GSK-137)Br. A', o \j y-N^'00^'T / X A.HN-Js’so

[0263] In certain embodiments, the BCL6 ligand is of formula IB10:where represents a bond to the linker.

[0264] In certain embodiments, the BCL6 ligand is a compound such as those described in United States Patent Publication No. 2020 / 0071297, the disclosure of which is herein incorporated by reference.BRD4-BCL6 CIPs

[0265] As reviewed above, in some embodiments, the CIPs provided herein comprise a first moiety that specifically binds to BCL6, and a second moiety that specifically binds to BRD4.

[0266] Chemical linkage of BCL-6 inhibitors, such as BI3812(PMID32275432), to BRD4 ligand compounds, e.g., JQ1, that then bind and induce proximity to the cell death (pro-apoptotic) promoters, such as those for TP53, PUMA and BIM, convert the inhibitor of cell death to an activator of cell death in cells expressing BRD4.

[0267] In certain embodiments, CIPs of interest having a BCL-6 (B-cell lymphoma 6) ligand and a BRD4 (bromodomain- containing 4) ligand include a compound selected from:WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601Compound I-16; Compound I-17;WSGR Docket No. 65514-707.601Compound I-20.

[0268] In some instances, the CIP is JWZ-7-7 having the structure provided in FIG. 2.

[0269] In some examples, CIPs having a BCL-6 (B-cell lymphoma 6) ligand and a BRD4 (bromodomain-containing 4) ligand can include one or more members selected from the following:WSGR Docket No. 65514-707.601WSGR Docket No. 65514-707.601CDK9-BCL6 CIPs

[0270] As reviewed above, in some embodiments, CIPs provided herein comprise a first moiety that specifically binds to BCL6, and a second moiety that specifically binds to CDK9. Chemical linkage of BCL-6 inhibitors, such as BI3812(PMID32275432), to CDK ligand compounds, e.g., CDK9 inhibitors, that then bind and induce proximity to the cell death (pro-apoptotic) promoters, such as those for TP53,WSGR Docket No. 65514-707.601PUMA and BIM, convert the inhibitor of cell death to an activator of cell death in cells having high concentrations of CDK9.

[0271] Specific CDK9-BCL6 CIPs finding use in embodiments of the disclosure include, but are not limited to:WSGR Docket No. 65514-707.601EXAMPLES

[0272] The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art.Example 1. A BCL6-BRD4 CIP induces apoptosis in a BCL6-high germinal center DLBCL cell line

[0273] SUDHL5, a BCL6-high germinal center DLBCL cell line, were obtained from the American Tissue Culture Collection (ATCC) and were cultured in RPMI-1640 + 10% FBS and Pen / Strep. 30,000 cells were plated in 100 microliters of media per well of a 96 well plate and treated with BCL6-BRD4 CIP compounds at the indicated concentrations (FIG.4) for 72 hours. 10 microliters of a resazurin-based indicator of cell viability (PrestoBlue, ThermoFisher #P50200) was added for 2 hours and the fluorescence ratio at 560 / 590 nm was measured. Background fluorescence of the medium alone was subtracted and each sample’s fluorescent signal was normalized against that of DMSO -treated cells. The results demonstrate that a BCL6-BRD4 CIP induced apoptosis of SUDHL5 cells (FIG. 4).Example 2. A BCL6-BRD4 CIP induces a pronounced transcriptional switch in BCL6-high germinal center DLBCL cells

[0274] 1 million SUDHL5 cells were treated with 10 nM BCL6-BRD4 CIP or DMSO for 8 hours. Cells were harvested and shipped on dry ice for total RNA extraction, library preparation, and bulk mRNAWSGR Docket No. 65514-707.601sequencing. The mRNA sequencing data (FIG. 5) demonstrates that treatment of SUDHL5 cells with a BCL6-BRD4 CIP induced a pronounced transcriptional switch. A prominent component of this response is induction of core apoptotic genes spanning both extrinsic and intrinsic pathways. In addition, the gene expression pattern showed strong induction of a stress / checkpoint program that is classically associated with p53-responsive and anti-proliferative genes, normally repressed by BCL6.

[0275] The mRNA sequencing data (FIG. 6) also showed a coordinated shutdown of hallmark GC identity genes in SUDHL5 cells treated with a BCL6-BRD4 CIP, consistent with collapse of the GC transcriptional program. Canonical GC markers, such as LM02, MEF2B, AICDA, SCIMP and SERPINA9 were significantly reduced. Because AICDA is predominantly expressed in GC B cells and is required for somatic hypermutation and class-switch recombination, its downregulation indicates suppression of core GC effector functions.Example 3. Cells expressing low levels of BCL6 are less sensitive to treatment with a BCL6-BRD4 CIP than cells expressing high levels of BCL6

[0276] CD14+human peripheral monocytes and CD19+human peripheral B cells, were obtained from the Stanford Blood Blank and were cultured in RPMI-1640 + 10% human AB Serum + 10 mM HEPES + 25 μM beta-mercaptoethanol + Pen / Strep. 500,000 cells were plated in 100 microliters of media per well of a 96 well plate and treated with BCL6-BRD4 CIP compounds at the indicated concentrations (FIG. 7) for 72 hours. 10 microliters of a resazurin-based indicator of cell viability (PrestoBlue, ThermoFisher #P50200) was added for 2 hours and the fluorescence ratio at 560 / 590 nm was measured. Background fluorescence of the medium alone was subtracted and each sample’s fluorescent signal was normalized against that of DMSO-treated cells. The results demonstrate that CD14+human peripheral monocytes and CD19+human peripheral B cells are four orders of magnitude (>10,000 fold) less sensitive to a BCL6-BRD4 CIP (FIG. 7) than BCL6-high, GC DLBCL cells (FIG. 4).

[0277] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WSGR Docket No. 65514-707.601CLAIMS WHAT IS CLAIMED IS:

1. A method of treating an autoimmune disease or disorder in a subject, the method comprising:administering to the subject a chemical inducer of proximity (CIP) which couples a BTB domain-containing protein or a transcriptional repressor expressed in B cell subpopulations with a modulator of gene regulation, in an amount effective to treat the autoimmune disease or disorder,thereby treating the autoimmune disease or disorder in the subject.

2. The method of claim 1, wherein the autoimmune disease or disorder is associated with presence of active, hyperactive, or ectopic germinal centers.

3. The method of claim 1 or 2, wherein the autoimmune disease or disorder is selected from the group consisting of: rheumatoid arthritis (RA), Sjogren’s syndrome (SS), immunoglobulin G4-related disease (IgG4-RD), juvenile arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, autoimmune thyroid disease (i.e. Graves Disease), multiple sclerosis, autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), Evan’s syndrome, systemic lupus erythematosus (SLE), dermatomyositis, scleroderma, organ rejection, Crohn’s disease, myasthenia gravis, diabetes type 1, diabetes type 2, Reiter’s syndrome, Neuromyelitis optica spectrum disorder (NMOSD), Pemphigus vulgaris, Anti-GBM (Goodpasture) disease, acquired hemophilia A, immune-mediated (acquired) TTP, seronegative enthesopathy and arthropathy (SEA) syndrome, prothrombotic autoantibody syndromes such as antiphospholipid syndrome (APS), psoriasis, and atopic dermatitis.

4. The method of claim 2 or 3, wherein, after the administering, levels of B cells are reduced.

5. The method of any one of claims 1-4, wherein the administering is selected from the group consisting of: oral administration, intravenous administration, intramuscular administration, intraarticular administration, subcutaneous administration, topical administration, and intralesional administration.

6. A method of reducing a level of B cells, the method comprising:contacting a B cell with a chemical inducer of proximity (CIP) which couples a BTB domain-containing protein or a transcriptional repressor expressed in B cell subpopulations with a modulator of gene regulation, such that the B cell undergoes apoptosis,thereby reducing the level of B cells.

7. The method of any one of claims 1-6, wherein the BTB domain- containing protein is or comprises BCL6.

8. The method of any one of claims 1-7, wherein the BTB domain- containing protein is or comprises a protein selected from Table 1.

9. The method of any one of claims 1-6, wherein the transcriptional repressor expressed in B cell subpopulations is selected from the group consisting of: PR domain containing 1 (PRDM1) and IRF4.

10. The method of any one of claims 1-9, wherein the modulator of gene regulation is or comprises BRD4.WSGR Docket No. 65514-707.60111. The method of any one of claims 1-10, wherein the modulator of gene regulation is or comprises CDK9.

12. The method of any one of claims 1-11, wherein the modulator of gene regulation is or comprises p300.

13. The method of any one of claims 1-12, wherein the modulator of gene regulation is or comprises a protein selected from Table 2.

14. The method of any one of claims 1-13, wherein the CIP has the structure of Formula I or Formula II:A-linker-B(Formula I); orA-B(Formula II),wherein A is a first moiety that specifically binds to the BTB domain- containing protein or the transcriptional repressor expressed in B cell subpopulations, andwherein B is a second moiety that specifically binds to the modulator of gene regulation.

15. The method of claim 14, wherein the linker is a chemical linker.

16. The method of claim 14 or 15, wherein the linker has a molecular weight ofless than about 2,000 g / mol.

17. The method of any one of claims 14-16, wherein the linker has a molecular weight of about 50 g / moL to about 2000 g / moL.

18. The method of any one of claims 14-17, wherein the linker has a LogP of less than about 10.

19. The method of any one of claims 14-18, wherein the linker has less than about 50 rotatable bonds.

20. The method of any one of claims 14-19, wherein the linker has a Topological Polar Surface Area (TPSA) of less than about 300.

21. The method of any one of claims 14-20, wherein the linker is asymmetrical, symmetrical, or a bond.

22. The method of any one of claims 14-21, wherein A is a small molecule compound.

23. The method of any one of claims 14-22, wherein B is a small molecule compound.

24. The method of any one of claims 1-23, wherein the CIP induces expression of at least one proapoptotic gene in a cell.

25. The method of claim 24, wherein the at least one proapoptotic gene is selected from the group consisting of: TP 53, PUMA (BBC3), BIM (BCL2L11), BID, BAX, BAK, BOK, BAD, HRK, BIK, BMP, and NOXA.

26. The method of any one of claims 1-25, wherein the BTB domain-containing protein or the transcriptional repressor expressed in B cell subpopulations, and the modulator of gene regulation are both endogenous proteins.WSGR Docket No. 65514-707.60127. The method of claim 26, wherein the BTB domain- containing protein or the transcriptional repressor expressed in B cell subpopulations and the modulator of gene regulation are both expressed in the same cell.

Images