Compositions, systems, and methods for modulating a target gene

Abstract

Provided is a method of regulating the expression of a target gene in a cell. Aspects of the method include contacting the cell with a compound having a first moiety covalently linked to a second moiety, wherein: (i) the first moiety exhibits specific binding to a first endogenous protein; (ii) the second moiety exhibits specific binding to a second endogenous protein different from the first endogenous protein; (iii) upon contact with the cell, the first endogenous protein and the second endogenous protein spatially complex with each other via the compound to effect a gain of function in the cell, whereby a process that is not normally regulated by either the first endogenous protein or the second endogenous protein is activated. Here, the first moiety targets BCL-6; the second moiety targets any one of an estrogen receptor, an androgen receptor, BRD4 or a cyclin-dependent kinase. TIFF2025517099000355.tif106159

Description

Technical Field

[0001] Government Rights This invention was made with government support under Contract No. CA163915, CA276167, and MH126720 awarded by the National Institutes of Health. The United States government has certain rights in this invention.

[0002] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 337,330, filed May 2, 2022; U.S. Provisional Patent Application No. 63 / 388,386, filed Jul. 12, 2022; U.S. Provisional Patent Application No. 63 / 406,128, filed Sep. 13, 2022; U.S. Provisional Patent Application No. 63 / 406,602, filed Sep. 14, 2022; and U.S. Provisional Patent Application No. 63 / 406,570, filed Sep. 14, 2022, each of which is hereby incorporated by reference in its entirety.

Background Art

[0003] Background Methods for controlling gene expression regulation are becoming increasingly important in a wide range of fields, such as, but not limited to, gene therapy, synthetic biology, plant management, environmental purification, management of bacteria and microorganisms, and synthetic artificial gene circuits. The control of gene expression holds great potential in the revolution of therapeutic drugs, animal models, and biotechnological processes, and is useful for integrating multiple input signals for the development of cell - based therapeutic drugs and animal models. Despite recent rapid progress, precise control of gene expression remains difficult due to unpredictability caused by unexpected interactions between biological components such as transcription factors. A fundamental goal in cell engineering is to express genes predictably and efficiently under precise control at desired levels. Such genetically engineered cells are highly promising for the progress of therapeutic drugs, diagnostic agents, animal models, and biotechnological processes.

[0004] To date, a variety of different gene modulation techniques for modulating gene expression in cells have been developed. Such gene modulation techniques include RNA interference, DNA editing and expression, and chemicals 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 by direct application to the medium, lipofection, electroporation, or viral transduction.

[0005] However, due to the broad availability of gene modulation for both research and therapeutic applications, the development of new methods for modulating the transcription of target genes in cells, specifically for modulating gene expression without genetic modification, remains an ongoing concern.

Summary of the Invention

[0006] Summary Provided are methods and compositions for modulating the expression of a target gene within a cell. Aspects of the method include contacting the cell with a compound having a first moiety covalently linked to a second moiety, wherein: (i) the first moiety exhibits specific binding to a first endogenous protein that binds to the target gene (or a region near the target gene, such as a promoter or regulatory region); (ii) the second moiety exhibits specific binding to a second endogenous protein that is different from the first endogenous protein; and (iii) upon contact with the cell, the first endogenous protein and the second endogenous protein spatially complex with each other via the compound to effect a gain of function in the cell. In some embodiments, the gain of function is characterized by modulating the expression of the target gene in a manner that is dependent on the presence of the second endogenous protein bound to the compound. Aspects of the method result in one or more beneficial features, such as, but not limited to, a gain of function being achieved by utilizing less than about 50% of the amount of the first and / or second endogenous protein present within the cell; mediation of a gain of function with an EC50 of less than about 1 micromolar; and modulation of the expression of the target gene in less than about 16 hours or about 16 hours.

[0007] Accordingly, in one aspect, provided herein is a compound of Formula I: BR-L-BC (I) wherein: BR is a ligand that specifically binds to bromodomain-containing protein 4 (BRD4); BC is a ligand that specifically binds to B cell lymphoma 6 (BCL-6) (or a homolog thereof); L is a linker or a pharmaceutically acceptable salt thereof is provided.

[0008] In another aspect, provided herein is a method of treating a subject for a malignant tumor, the method comprising administering to the subject a transcriptional chemical inducer of proximity (TCIP) that links BCL-6 and BRD4 in an amount effective to treat the subject for the malignant tumor.

[0009] In another aspect, provided herein is a transcriptional chemical inducer of proximity (TCIP) for treating a malignant tumor, the TCIP comprising a first ligand that specifically binds to BCL-6 and a second ligand that specifically binds to BRD4; and a pharmaceutical composition comprising a delivery vehicle.

[0010] In yet another aspect, provided herein is a method of treating a subject for diffuse large B-cell lymphoma (DLBCL), the method comprising administering to the subject a chemical inducer of proximity (CIP) that links BCL-6 and an estrogen receptor in an amount effective to treat the subject for DLBCL.

[0011] In yet another aspect, provided herein is a method of treating a subject for a malignant tumor, the method comprising administering to the subject a transcriptional chemical inducer of proximity (TCIP) that links BCL-6 (or a homolog thereof) and a cyclic-dependent kinase in an amount effective to treat the subject for the malignant tumor.

[0012] In yet another aspect, provided herein is a transcriptional chemical inducer of proximity (TCIP) for treating a malignant tumor, the TCIP comprising a first ligand that specifically binds to BCL-6 (or a homolog thereof) and a second ligand that specifically binds to CDK.

[0013] In yet another aspect, provided herein is a transcription-based proximity chemical inducer (TCIP) for treating a malignant tumor, comprising a first ligand that specifically binds to BCL-6 (or a homolog thereof) and a second ligand that specifically binds to CDK; and a pharmaceutical composition comprising a delivery vehicle.

[0014] In yet another aspect, provided herein is a method of treating a subject for a malignant tumor, the method comprising administering to the subject a transcription-based proximity chemical inducer (TCIP) that links BCL-6 (or a homolog thereof) and an androgen receptor (AR) in an amount effective to treat the subject for the malignant tumor. In yet another aspect, provided is a transcription-based proximity chemical inducer (TCIP) for treating a malignant tumor, comprising a first ligand that specifically binds to BCL-6 (or a homolog thereof), wherein the first ligand is linked by a linker to a second ligand that specifically binds to AR.

[0015] In yet another aspect, provided herein is a transcription-based proximity chemical inducer (TCIP) for treating a malignant tumor, comprising a first ligand that specifically binds to BCL-6 (or a homolog thereof), wherein the first ligand is linked by a linker to a second ligand that specifically binds to AR; and a pharmaceutical composition comprising a delivery vehicle.

[0016] In yet another aspect, provided herein is a method of regulating the expression of a target gene in a cell comprising a first endogenous protein and a second endogenous protein, the method comprising contacting the cell with a compound having a first moiety covalently linked to a second moiety, wherein: (a) the first moiety exhibits specific binding to a first endogenous protein that binds to the target gene or a region near the target gene (e.g., a promoter, a regulatory region); (b) the second moiety exhibits specific binding to a second endogenous protein that is different from the first endogenous protein; (c) upon contact with the cell, the first endogenous protein and the second endogenous protein spatially complex with each other via the compound to effect a gain of function in the cell, the gain of function modulating the expression of the target gene in a manner that is dependent on the presence of the second endogenous protein bound to the compound, and the gain of function is achieved by utilization of less than about 50% of the amount of the second endogenous protein present in the cell.

[0017] In yet another aspect, provided herein is a method of regulating the expression of a target gene in a cell comprising a first endogenous protein and a second endogenous protein, the method comprising contacting the cell with a compound having a first moiety covalently linked to a second moiety, wherein: (a) the first moiety exhibits specific binding to a first endogenous protein that binds to the target gene; (b) the second moiety exhibits specific binding to a second endogenous protein that is different from the first endogenous protein; (c) upon contact with the cell, the first endogenous protein and the second endogenous protein spatially complex with each other via the compound to effect a gain of function in the cell, the gain of function modulating the expression of the target gene in a manner that is dependent on the presence of the second endogenous protein bound to the compound, and the compound has an EC 50 mediating the gain of function of less than about 1 micromolar.

[0018] In yet another aspect, provided herein is a method of modulating the expression of a plurality of target genes in a cell, the method comprising contacting the cell with a compound having a first moiety covalently linked to a second moiety, wherein: (a) the first moiety exhibits specific binding to a first endogenous protein that reduces the expression of the target gene in the absence of the compound; (b) the second moiety exhibits specific binding to a second endogenous protein that enhances the expression of a further target gene in the absence of the compound; and (c) upon contact with the cell, the first endogenous protein and the second endogenous protein spatially pair with each other via the compound to effect a gain of function in the cell, the gain of function characterized by (i) enhanced expression of the one target gene as compared to the absence of the compound, and (ii) reduced expression of the further target gene as compared to the absence of the compound.

[0019] In yet another aspect, provided herein is a method of modulating the expression of a target gene in a cell, the method comprising contacting the cell in an effective amount with a compound having a first moiety covalently linked to a second moiety, wherein: (a) the first moiety exhibits specific binding to a first endogenous protein that binds to the target gene; (b) the second moiety exhibits specific binding to a second endogenous protein different from the first endogenous protein; and (c) upon contact with the cell, the first endogenous protein and the second endogenous protein bind to the compound to form a complex, effecting a gain of function in the cell, the gain of function characterized by modulating the expression of the target gene in a manner dependent on the presence of the second endogenous protein bound to the compound, wherein the expression of the target gene is modulated less than about 16 hours or at about 16 hours after the contact.

[0020] In yet another aspect, provided herein is a compound of formula (I): A-B(I) wherein: In the formula: (a) A is a first moiety that exhibits specific binding to a first endogenous protein within the cell that binds to the target gene; (b) B is a second moiety that exhibits specific binding to a second endogenous protein within the cell that is different from the first endogenous protein; (c) the compound spatially forms a complex with the first endogenous protein and the second endogenous protein to bring about a gain of function in the cell, wherein the gain of function modulates the expression of the target gene in a manner that is dependent on the presence of the second endogenous protein bound to the compound, where: (i) the gain of function is achieved by utilization of less than about 50% of the amount of the second endogenous protein present in the cell; (ii) the compound mediates the gain of function with an EC less than about 1 micromolar; and / or 50 (iii) the first endogenous protein reduces the expression of the target gene in the absence of the compound, the second endogenous protein enhances the expression of the target gene further in the absence of the compound, and the gain of function is characterized by (iii(a)) the expression of the target gene being enhanced compared to the absence of the compound and (iii(b)) the expression of the target gene being further reduced compared to the absence of the compound, A compound is provided.

[0021] In yet another aspect, herein, Formula (I): A - B (I) A compound of, wherein: (a) A is a first moiety that exhibits specific binding to a first endogenous protein within the cell that binds to the target gene; (b) B is a second moiety that exhibits specific binding to a second endogenous protein within the cell that is different from the first endogenous protein; ​(c) The compound binds to a first endogenous protein and a second endogenous protein to form a complex, and the complex can modulate the expression of a target gene in a manner dependent on the presence of the second endogenous protein in the complex. The expression of the target gene is modulated by the complex in less than about 16 hours or about 16 hours. Provided is a compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0022]

Figure 1

Figure 2

Figure 3

Figure 4A

Figure 4B

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14A

Figure 14B

Figure 14C-1

Figure 14C-2

Figure 15

Figure 16

Figure 17

Figure 18A-1

Figure 18A-2

Figure 18A-3

Figure 18A-4

Figure 18A-5

Figure 18B

Figure 19

Figure 20

Figure 21

Figure 22-1

Figure 22-2

Figure 22-3

Figure 22-4

Figure 23-1

Figure 23-2

Figure 23-3

Figure 23-4

Figure 24

Figure 25

Figure 26

Figure 27

Figure 28

Figure 29

Figure 30

Figure 31

Figure 32

Figure 33

Figure 34

Figure 35

Figure 36

Figure 37

Figure 38

Figure 39

Figure 40

DETAILED DESCRIPTION OF THE INVENTION

[0023] DETAILED DESCRIPTION As used herein, the term “alkyl” alone or as part of another substituent refers to a branched or straight-chain monovalent saturated hydrocarbon group obtained by removal of one hydrogen atom from one carbon atom of the parent alkane. Typical alkyl groups include, but are not limited to, methyl; ethyl, propyl such as propane-1-yl or propane-2-yl; and butyl such as butane-1-yl, butane-2-yl, 2-methyl-propane-1-yl or 2-methyl-propane-2-yl. In some embodiments, the alkyl group contains 1 to 20 carbon atoms. In other embodiments, the alkyl group contains 1 to 10 carbon atoms. In yet other embodiments, the alkyl group contains 1 to 6 carbon atoms, such as 1 to 4 carbon atoms.

[0024] "Alkanil", alone or as part of another substituent, refers to a branched, straight-chain, or cyclic saturated alkyl group obtained by removing one hydrogen atom from one carbon atom of an alkane. Typical alkanil groups include, but are not limited to, methanyl; ethanil; propanil, such as propane-1-yl, propane-2-yl (isopropyl), cyclopropane-1-yl, etc.; butanil, such as butane-1-yl, butane-2-yl (sec-butyl), 2-methyl-propane-1-yl (isobutyl), 2-methyl-propane-2-yl (t-butyl), cyclobutane-1-yl, etc.

[0025] "Alkylene" typically refers to a branched or unbranched saturated hydrocarbon chain having from 1 to 40 carbon atoms, more typically from 1 to 10 carbon atoms, and even more typically from 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -), etc.

[0026] "Alkenyl", alone or as part of another substituent, denotes a branched, straight-chain or cyclic unsaturated alkyl group having at least one carbon-carbon double bond obtained by removal of one hydrogen atom from one carbon atom of an alkene. This group can be in either a cis or trans conformation with respect to the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyl, such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyl, such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.

[0027] "Alkynyl", alone or as part of another substituent, denotes a branched, straight-chain or cyclic unsaturated alkyl group having at least one carbon-carbon triple bond obtained by removal of one hydrogen atom from one carbon atom of an alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl, such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyl, such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

[0028] "Acyl", alone or as part of another substituent, denotes a group of -C(O)R 30 wherein R 30is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl as defined herein and substituted variants thereof. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, piperonyl, propionyl, succinyl and malonyl.

[0029] The term "aminoacyl" refers to a -C(O)NR 21 R 22 group, where R 21 and R 22 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and optionally R 21 and R 22 are linked and together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group, and the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0030] "Alkoxy" alone or as part of another substituent refers to the atomic group -OR 31 where R 31 represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.

[0031] "Alkoxycarbonyl" alone or as part of another substituent refers to -C(O)OR 31represents an atomic group, where R 31 represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, cyclohexyloxycarbonyl, and the like.

[0032] "Aryl" alone or as part of another substituent represents a monovalent aromatic hydrocarbon atomic group obtained by removing one hydrogen atom from one carbon atom of an aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, preiaden, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. In some specific embodiments, the aryl group contains 6 to 20 carbon atoms. In some specific embodiments, the aryl group contains 6 to 12 carbon atoms. Examples of aryl groups are phenyl and naphthyl.

[0033] "Arylalkyl" alone or as part of another substituent represents a carbon atom, typically a terminal carbon atom or sp 3An acyclic alkyl atomic group in which one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl group is shown. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. When a specific alkyl moiety is intended, the nomenclature arylalkanyl, arylalkenyl, and / or arylalkynyl is used. In some specific embodiments, the arylalkyl group is (C 7 ~C 30 ) arylalkyl, for example, the alkanoyl, alkenyl, or alkynyl moiety of the arylalkyl group is (C 1 ~C 10 ), and the aryl moiety is (C 6 ~C 20 ). In some specific embodiments, the arylalkyl group is (C 7 ~C 20 ) arylalkyl, for example, the alkanoyl, alkenyl, or alkynyl moiety of the arylalkyl group is (C 1 ~C 8 ), and the aryl moiety is (C 6 ~C 12 ).

[0034] "Arylaryl", alone or as part of another substituent, refers to a monovalent hydrocarbon group obtained by removing one hydrogen atom from one carbon atom of a ring system in which two or more identical or non-identical aromatic ring systems are directly linked together by a single bond, where the number of such direct ring junctions is one less than the number of aromatic ring systems involved. Typical arylaryl groups include, but are not limited to, biphenyl, triphenyl, phenyl-napthyl, binaphthyl, biphenyl-naphthyl, and the like. When the number of carbon atoms of an arylaryl group is specified, this number indicates the carbon atoms constituting each aromatic ring. For example, (C 5 ~C 14)Arylaryl is an arylaryl group in which each aromatic ring contains 5 to 14 carbons, such as biphenyl, triphenyl, binaphthyl, phenylnaphthyl, etc. In some specific embodiments, each aromatic ring system of the arylaryl group is independently (C 5 ~C 14 ) aromatic. In some specific embodiments, each aromatic ring system of the arylaryl group is independently (C 5 ~C 10 ) aromatic. In some specific embodiments, each aromatic ring system is the same, such as biphenyl, triphenyl, binaphthyl, trinaphthyl, etc.

[0035] "Cycloalkyl" alone or as part of another substituent refers to a saturated or unsaturated cyclic alkyl group. When a specific saturation level is intended, the nomenclature "cycloalkanil" or "cycloalkenyl" is used. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc. In some specific embodiments, the cycloalkyl group is (C 3 ~C 10 ) cycloalkyl. In some specific embodiments, the cycloalkyl group is (C 3 ~C 7 ) cycloalkyl.

[0036] "Cycloheteroalkyl" or "heterocyclyl", alone or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl group in which one or more carbon atoms (and any attendant hydrogen atoms) are independently replaced by the same or different heteroatoms. Exemplary heteroatoms that can replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. When a specific level of saturation is intended, the nomenclature "cycloheteroalkanyl" or "cycloheteroalkenyl" is used. Exemplary cycloheteroalkyl groups include, but are not limited to, groups derived from epoxides, aziridines, thiiranes, imidazolidines, morpholines, piperazines, piperidines, pyrazolidines, pyrrolidines, quinuclidines, etc.

[0037] "Heteroalkyl, heteroalkanyl, heteroalkenyl and heteroalkynyl", alone or as part of another substituent, each refers to an alkyl, alkanyl, alkenyl and alkynyl group in which one or more carbon atoms (and any attendant hydrogen atoms) are independently replaced by the same or different heteroatom groups. Exemplary heteroatom groups that can be included in these groups include, but are not limited to, -O-, -S-, -S-S-, -O-S-, -NR 37 R 38 -, =.N-N=, -N=N-, -N=N-NR 39 R 40 -, -PR 41 -, -P(O) 2 -, -POR 42 -, -O-P(O) 2 -, -S-O-, -S-(O)-, -SO 2 -, -SnR 43 R 44 -, etc., where R 37 、R 38 、R 39 、R 40 、R 41 、R 42 、R 43 and R 44is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.

[0038] "Heteroaryl" alone or as part of another substituent refers to a monovalent heteroaromatic atomic group obtained by removing one hydrogen atom from one atom of a heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, acridine, alstonine, carbazole, β-carboline, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolidine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, benzodioxole, and groups derived therefrom. In some specific embodiments, the heteroaryl group is a 5- to 20-membered heteroaryl. In some specific embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl. In some specific embodiments, the heteroaryl group is derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.

[0039] "Heteroarylalkyl" alone or as part of another substituent refers to a carbon atom, typically a terminal carbon atom or sp 3It represents an acyclic alkyl atomic group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a heteroaryl group. When a specific alkyl moiety is intended, the nomenclature of heteroarylalkanyl, heteroarylalkenyl, and / or heteroryl alkynyl is used. In some specific embodiments, the heteroarylalkyl group is a 6- to 30-membered heteroarylalkyl, for example, the alkaniyl, alkenyl, or alkynyl moiety of the heteroarylalkyl is 1 to 10 members, and the heteroaryl moiety is a 5- to 20-membered heteroaryl. In some specific embodiments, the heteroarylalkyl group is a 6- to 20-membered heteroarylalkyl, for example, the alkaniyl, alkenyl, or alkynyl moiety of the heteroarylalkyl is 1 to 8 members, and the heteroaryl moiety is a 5- to 12-membered heteroaryl.

[0040] "Aromatic ring system" refers to an unsaturated cyclic or polycyclic ring system having a conjugated π electron system, either alone or as part of another substituent. Specifically included in the definition of "aromatic ring system" are, for example, fused ring systems in which one or more rings such as fluorene, indane, indene, phenalene are aromatic and one or more rings are saturated or unsaturated. Typical aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, preiaden, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, etc.

[0041] "Heteroaromatic ring system" refers to an aromatic ring system in which one or more carbon atoms (and accompanying hydrogen atoms if any) are independently replaced by the same or different heteroatoms, either alone or as part of another substituent. Typical heteroatoms that can replace carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included in the definition of "heteroaromatic ring system" are fused ring systems in which one or more rings, such as, for example, arsindole, benzodioxane, benzofuran, chroman, chromene, indole, indoline, xanthene, etc., are aromatic and one or more rings are saturated or unsaturated. Typical heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, β-carboline, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolidine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, etc.

[0042] "Substituted type" refers to a group in which one or more hydrogen atoms are independently replaced by the same or different substituents (one or more). Typical substituents include, but are not limited to, alkylenedioxy (e.g., methylenedioxy), -M, -R 60 , -O - , =O, -OR 60 , -SR 60 , -S - , =S, -NR 60 R 61 , =NR 60 , -CF 3 , -CN, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3, -S(O) 2 O-, -S(O) 2 OH, -S(O) 2 R 60 , -OS(O) 2 O - , -OS(O) 2 R 60 , -P(O)(O - ) 2 , -P(O)(OR 60 )(O - ), -OP(O)(OR 60 )(OR 61 ), -C(O)R 60 , -C(S)R 60 , -C(O)OR 60 , -C(O)NR 60 R 61 , -C(O)O-, -C(S)OR 60 , -NR 62 C(O)NR 60 R 61 , -NR 62 C(S)NR 60 R 61 , -NR 62 C(NR 63 )NR 60 R 61 and -C(NR 62 )NR 60 R 61 are included, where M is halogen; R 60 , R 61 , R 62 and R 63 are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 60 and R 61 together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R 64 and R 65is independently hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 64 and R 65 are joined together with the nitrogen atom to which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring. In some specific embodiments, the substituents are -M, -R 60 , =O, -OR 60 , -SR 60 , -S - , =S, -NR 60 R 61 , =NR 60 , -CF 3 , -CN, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O) 2 R 60 , -OS(O) 2 O - , -OS(O) 2 R 60 , -P(O)(O - ) 2 , -P(O)(OR 60 )(O - ), -OP(O)(OR 60 )(OR 61 ), -C(O)R 60 , -C(S)R 60 , -C(O)OR 60 , -C(O)NR 60 R 61 , -C(O)O-, -NR 62 C(O)NR 60 R 61 include. In some specific embodiments, the substituents are -M, -R 60 , =O, -OR 60 , -SR 60 , -NR 60 R 61 , -CF 3 , -CN, -NO 2 , -S(O) 2 R 60 , -P(O)(OR 60 )(O -)、 -OP(O)(OR 60 )(OR 61 )、 -C(O)R 60 、 -C(O)OR 60 、 -C(O)NR 60 R 61 、 -C(O)O - and the like. In some specific embodiments, the substituents are -M, -R 60 、 =O、 -OR 60 、 -SR 60 、 -NR 60 R 61 、 -CF 3 、 -CN、 -NO 2 、 -S(O) 2 R 60 、 -OP(O)(OR 60 )(OR 61 )、 -C(O)R 60 、 -C(O)OR 60 、 -C(O)O - and the like, where R 60 、 R 61 and R 62 are as defined above. For example, the substituted group may have 1, 2 or 3 substituents selected from a methylenedioxy substituent or a halogen atom, a (1-4C) alkyl group and a (1-4C) alkoxy group.

[0043] Provided herein are compositions, systems, and methods for modulating the expression of a target gene in a target cell. The compositions, systems, and methods are used to modulate the expression of a target gene in a target cell by spatially juxtaposing different endogenous proteins expressed by the target cell such that a target gene that would not normally be regulatable by a protein in the absence of a compound is made regulatable by the protein. The compositions, systems, and methods generally each involve a compound that specifically binds to at least a first endogenous protein and a second different endogenous protein expressed by the target cell. The first endogenous protein is generally a protein that can bind to a target gene or a region near the target gene, such as a promoter or regulatory region, and serves as an anchor for the complex. The second endogenous protein is a protein that does not substantially regulate the expression of the target gene in the absence of the compound but can regulate the expression of the target gene when recruited to the target gene or a region near the target gene by the compound. Advantageously, the compositions, systems, and methods provided herein do not require any genetic modification of the target cell. Instead, the compositions, systems, and methods provided herein rely on the presence of proteins that are endogenously expressed in the target cell. Also, the compound is generally a small molecule that can be administered to a subject (e.g., by oral administration, intravenous administration, etc.).

[0044] It is to be understood that the present disclosure is not limited to the specific aspects described, and thus, of course, can be various. Also, since the scope of the present disclosure is limited only by the appended claims, it is to be understood that the terminology used herein is for the purpose of describing specific aspects only and is not intended to be limiting.

[0045] When a range of values is indicated, each value intervening between the upper and lower limits of the range, down to one tenth of the unit of the lower limit and any other value or intervening value described within the stated range are to be understood as being included in the invention, unless clearly stated otherwise in the text. The upper and lower limits of such a smaller range may independently be included in the smaller range and are also included in the invention, subject to the condition that there may be limiting values expressly excluded in the stated range. When the stated range includes one or both of the limiting values, ranges excluding either or both of the included limiting values are also included in the invention.

[0046] The terms “about” or “approximately” generally mean within the range of error tolerable for a particular value as measured or determined by one of ordinary skill in the art, which may depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean one or more standard deviations greater than 1 for each instance of practice in the art. Alternatively, “about” can mean within a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, especially with respect to biological systems or processes, the term can mean within a range of preferably up to 5-fold, more preferably up to 2-fold of the magnitude of the value. When specific values are set forth in this application and the claims, the term “about” is assumed, unless otherwise stated, to mean within the range of error tolerable for the specific value.

[0047] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, but representative examples of methods and materials are described herein.

[0048] All publications and patents cited in this specification are hereby incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference, and are incorporated by reference herein to disclose and describe the methods and / or materials related to the cited publications. The citation of any publication is for the purpose of disclosing that it is prior to the filing date of this application, and should not be construed as an admission that the present invention is temporally prior to such publication on the grounds of a prior invention. Further, the disclosed dates may be different from the actual publication dates and may need to be individually verified.

[0049] It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It should further be noted that the claims may be in draft form and may exclude any optional element. Therefore, this description is intended to serve as a basis for the use of exclusive terms such as "solely", "only", etc. or the use of "negative" limitations in relation to the recitation of claim components.

[0050] The section headings used in this specification are for organizational purposes only and should not be construed as limiting the subject matter described.

[0051] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual aspects described and illustrated herein has separate and independent components and features, and such components and features can be readily separated from the features of any other of the several aspects or combined with the features of any other of the several aspects without departing from the scope or spirit of the present invention. Any method described may be performed in the order of events described or in any other logically possible order.

[0052] The apparatus and method are described or would be described by functional description for grammatical fluidity, but the claims should not necessarily be construed as being limited to any means or step limitations unless clearly made in accordance with 35 U.S.C. § 112. Instead, they should be consistent with the meaning of the terms and the full scope of equivalents shown by the claims under the doctrine of fair equivalents. It should be clearly understood that when the claims are clearly made in accordance with 35 U.S.C. § 112, they should be consistent with the full statutory equivalents under 35 U.S.C. § 112.

[0053] Its systems, compositions and methods for regulating the expression of a target gene In one aspect, provided herein is a method for regulating the expression of a target gene in a cell comprising a first endogenous protein and a second endogenous protein, the method comprising contacting the cell with a compound having a first moiety linked (e.g., by covalent bond) to a second moiety, wherein: (a) the first moiety exhibits specific binding to the first endogenous protein, and the first endogenous protein binds to the target gene or a region near the target gene (e.g., a promoter, a regulatory region, etc.); (b) the second moiety exhibits specific binding to a second endogenous protein different from the first endogenous protein; (c) upon contact with the cell, the first endogenous protein and the second endogenous protein spatially complex with each other via the compound to effect a gain of function in the cell, wherein the gain of function modulates the expression of the target gene in a manner dependent on the presence of the second endogenous protein bound to the compound. The method is further defined in that the gain of function is achieved by utilizing less than about 50% of the amount of the second endogenous protein present in the cell.

[0054] In another aspect, provided herein is a method for regulating the expression of a target gene in a cell, the method comprising contacting the cell with a compound having a first moiety covalently linked to a second moiety, wherein: (a) the first moiety exhibits specific binding to a first endogenous protein, and the first endogenous protein binds to the target gene or a region near the target gene (e.g., a promoter, a regulatory region, etc.); (b) the second moiety exhibits specific binding to a second endogenous protein that is different from the first endogenous protein; (c) upon contact with the cell, the first endogenous protein and the second endogenous protein spatially form a complex with each other via the compound, resulting in a gain of function in the cell, wherein the gain of function modulates the expression of the target gene in a manner dependent on the presence of the second endogenous protein bound to the compound. The method further defines that the compound mediates the gain of function with an EC50 of less than about 1 micromolar.

[0055] In another aspect, provided herein is a method for regulating the expression of a plurality of target genes in a cell, the method comprising contacting the cell with a compound having a first moiety covalently linked to a second moiety, wherein: (a) the first moiety exhibits specific binding to a first endogenous protein, and the first endogenous protein reduces the expression of the target gene in the absence of the compound; (b) the second moiety exhibits specific binding to a second endogenous protein, and the second endogenous protein enhances the expression of a further target gene in the absence of the compound; (c) upon contact with the cell, the first endogenous protein and the second endogenous protein spatially pair with each other via the compound, resulting in a gain of function in the cell. The method further defines that the gain of function is characterized by: (i) the expression of the one target gene being enhanced compared to its expression in the absence of the compound; and (ii) the expression of the further target gene being reduced compared to its expression in the absence of the compound.

[0056] In another aspect, provided herein is a method of regulating the expression of a target gene in a cell, the cell comprising a first endogenous protein and a second endogenous protein, the method comprising contacting the cell with a compound having a first moiety covalently linked to a second moiety in an effective amount, wherein: (a) the first moiety exhibits specific binding to the first endogenous protein, and the first endogenous protein binds to the target gene or a region near the target gene (e.g., a promoter, a regulatory region); (b) the second moiety exhibits specific binding to a second endogenous protein different from the first endogenous protein; and (c) upon contact with the cell, the first endogenous protein and the second endogenous protein bind to the compound to form a complex, resulting in a gain of function in the cell, wherein the gain of function modulates the expression of the target gene in a manner dependent on the presence of the second endogenous protein bound to the compound. The method further provides that the expression of the target gene is modulated less than about 16 hours or at about 16 hours after the contact.

[0057] Also provided herein are compositions and systems suitable for practicing any of the foregoing methods, as further described herein.

[0058] As summarized above, the present disclosure provides a method for regulating the expression of a target gene in a cell, as well as a system and composition for realizing the same. The method can be considered an inducible method for regulating the expression of the target gene. Since the method is inducible, the regulation of the expression of the target gene is not constitutive, but occurs in response to a stimulus added to the cell, such as the supply of a compound as described in more detail below. Since the method is an inducible method for regulating the expression of the target gene, this is a method of changing the expression or expression profile of the target gene in some manner, for example, enhancing the expression of the target gene or reducing the expression of the target gene. The magnitude of the change in expression (compared to an appropriate control, such as the same system in the absence of the compound) can vary, and in some cases, the magnitude of the change, such as enhancement or reduction, is more than 2-fold, for example, more than 5-fold, for example, more than 10-fold. The target gene can be any gene as described herein or known in the art. The target gene can be a wild-type gene or a mutant gene.

[0059] As summarized above, the present disclosure provides a method for regulating the expression of a target gene (e.g., but not limited to, the BCL6 target gene). The term gene refers to a genomic region encoding a functional RNA, such as a non-coding RNA, microRNA, enhancer RNA, or RNA that can be translated into a protein product. The term gene is used in its conventional sense to refer to a region or domain of a chromosome that includes not only the coding sequence in the form of exons separated by introns, but also regulatory sequences, such as enhancers / silencers, promoters, terminators, non-coding RNAs, microRNAs, etc.

[0060] The specific target genes that are the focus of a given method can vary. A target gene can be any gene of interest whose expression is modulated by the compositions, systems, and methods provided herein. In some cases, the target gene is a gene whose expression is enhanced. Non-limiting examples of genes whose expression is enhanced by the compositions, systems, and methods provided herein include apoptosis-promoting genes (e.g., PUMA (BBC3), BIM (BCL2L11), BID, BAX, BAK, BOK, BAD, HRK, BIK, BMF, and NOXA (PMAIP1)). In some cases, the target gene is a gene whose expression is inhibited or reduced. Non-limiting examples of genes whose expression is inhibited or reduced by the compositions, systems, and methods provided herein include anti-apoptosis genes, such as BCL6, and genes that promote cell survival and proliferation, such as MYC. In some cases, the target gene is a therapeutic gene (e.g., but not limited to, rate-limiting enzymes (e.g., TPH2), haploinsufficient genes (e.g., ARID1B), etc.) that can produce a beneficial effect on the cell or subject upon expression (e.g., upregulation or enhancement). In some cases, the target gene is a gene whose expression has a harmful effect on the cell or subject and / or causes a disease or disorder in the subject (e.g., a mutant gene), and is a gene whose expression is inhibited or reduced by the compositions, systems, and methods provided herein. In some cases, the target gene is an overexpressed gene (e.g., but not limited to, oncogenes (e.g., MYC), trisomy genes (e.g., chromosome 21 genes), amplified genes, etc.) whose expression is inhibited or reduced by the compositions, systems, and methods provided herein.

[0061] The above gene categories are merely illustrative of the types of genes that can be target genes of the subject methods. Any gene whose expression is regulated (e.g., enhanced, reduced) by the compositions, systems and methods provided herein can be a target gene. Further examples of target genes include, but are not limited to, developmental genes (e.g., adhesion molecules, cyclin kinase inhibitors, cytokines / lymphokines and their receptors, tumor immunogenic determinants, growth / differentiation factors and their receptors, immune checkpoint receptors and ligands, neurotransmitters and their receptors); oncogenes (e.g., ABL1, BCL1, BCL2, BCL6, CBFA2, CBL, CSF1R, ERBA, ERBB, ERBB2, ETS1, ETS1, ETV6, FGR, FOS, FYN, HCK, HRAS, JUN, KRAS, LCK, LYN, MDM2, MLL, MYB, MYC, MYCL1, MYCN, NRAS, PIM1, PML, RET, SRC, TAL1, TCL3 and YES); tumor suppressor genes (e.g., APC, BRCA1, BRCA2, MADH4, MCC, NF1, NF2, RB1, TP53 and WT1); enzymes (e.g., ACC synthase and oxidase, ACP desaturase and hydroxylase, ADP-glucose pyrophorylase, ATPase, alcohol dehydrogenase, amylase, amyloglucosidase, catalase, cellulase, chalcone synthase, chitinase, cyclooxygenase, decarboxylase, dextrinase, DNA polymerase and RNA polymerase, galactosidase, glucanase, glucose oxidase, granule-bound starch synthase, GTPase, helicase, hemicellulase, integrase, inulinase, invertase, isomerase, kinase, lactase, Lpase, lipoxygenase, lysozyme, nopaline synthase, octopine synthase, pectin esterase, peroxidase, phosphatase, phospholipase, phosphorylase, phytase, plant growth regulator synthase, polygalacturonase, proteinase and peptidase, pullulanase, recombinase, reverse transcriptase, RUBISCO, topoisomerase and xylanase);Chemokines (e.g., CXCR4, CCR5), telomerase RNA element, vascular endothelial growth factor (VEGF), VEGF receptor, tumor necrosis factor, nuclear factor kappa B, transcription factor, cell adhesion molecule, insulin-like growth factor, transforming growth factor beta family member, cell surface receptor, RNA binding protein (e.g., small nuclear RNA, RNA transport factor), translation factor, telomerase reverse transcriptase), and the like.

[0062] As described above, in some cases, the target gene is a therapeutic gene (e.g., a gene that, when expressed, has a beneficial effect on a cell or a subject). Examples of therapeutic target genes suitable for regulation using the compositions, systems, and methods provided herein include, but are not limited to, those shown in Table 1 below.

[0063] (Table 1) Examples of therapeutic target genes TIFF2025517099000002.tif208146

[0064] In some cases, the target gene is a non-coding gene. Examples of non-coding genes of interest include, but are not limited to, those shown in Table 2.

[0065] (Table 2) Non-limiting examples of non-coding genes TIFF2025517099000003.tif70146

[0066] Genes that can be targeted by one or more compounds (e.g., proximity chemical inducer (CIP), transcription system proximity chemical inducer (TCIP), etc.) as provided herein are also shown in PCT application number PCT / US2021 / 058231, published as WO2022 / 098989; the disclosure of which is incorporated herein by reference in its entirety.

[0067] In some cases, the target gene that can be regulated by the systems, compositions and methods provided herein can be an intrachromosomal gene or an extrachromosomal gene. In some cases, the target gene can be an endogenous gene. Alternatively or additionally, the target gene can be a heterologous gene, such as a gene present in a plasmid or vector that is introduced into a cell (e.g., transfected by a transfection agent, transduced by a virus, etc.). Prior to being regulated by the systems, compositions and methods provided herein, such heterologous genes may or may not be integrated into the genome of the cell.

[0068] As described herein, the compositions, systems, and methods provided herein involve the use of a compound that has at least a first moiety and a second moiety, where the first moiety specifically binds to a first endogenous protein expressed in a target cell and the second moiety specifically binds to a second endogenous protein expressed in the target cell. The moieties of the compound may sometimes be referred to as ligands throughout the present disclosure, and the terms "moiety" and "ligand" (or "moieties" and "ligands") may be used interchangeably herein. The first endogenous protein and the second endogenous protein each originate from and are expressed within the cell. In particular, both the first endogenous protein and the second endogenous protein are present within or expressed within the cell at the time the compounds disclosed herein (e.g., CIP or TCIP, etc.) are administered. The compositions, systems, and methods provided herein generally do not require co - exogenous introduction (e.g., transfection, transduction, etc.) of the first and / or second endogenous proteins into the cell to which the subject compound is administered to achieve a gain of function. The compositions, systems, and methods provide specificity such that a gain of function is achieved only in certain target cells in which both the first endogenous protein and the second endogenous protein are expressed. In some embodiments, the compounds of the present disclosure comprise at least a first moiety and a second moiety that bind to at least a first endogenous protein and a second endogenous protein, thereby forming a ternary complex of the compound, the first endogenous protein, and the second endogenous protein. The first endogenous protein and the second endogenous protein are spatially proximate and associated with each other.

[0069] This ternary complex (e.g., of the compound, a first endogenous protein, and a second endogenous protein) is an unnatural complex that would not normally be present in the cell in the absence of both the compound and the first and second endogenous proteins. Thus, such a compound may be referred to herein as a "proximity chemical inducer" or "CIP" in some cases. In some cases, for example, when the compound binds to an endogenous anchor transcription factor and an endogenous transcription modulation factor, the compound may be referred to herein as a "transcriptional chemical inducer of proximity", "transcription chemical inducer of proximity", or "TCIP". The first and second moieties of the compound can be derived from naturally occurring substances and / or synthetic substances. Applicable and readily observable or measurable criteria for selecting the moiety include, but are not limited to: (A) the moiety is physiologically acceptable (e.g., it is not overly toxic to the cell or animal in which it is used); (B) the moiety has a reasonable therapeutic dosage range (e.g., as confirmed by obtaining a desired expression profile of the target gene or a desired cellular activity in the cell); (C) the moiety can pass through the cell membrane or other membranes as needed; and / or (D) the moiety binds to one or more target domains of the first and / or second endogenous proteins as provided herein, e.g., an endogenous anchor transcription factor and / or an endogenous transcription modulation factor. For example, a desirable criterion is that the compound is chemically stable and has the ability to form the complex. In some instances, the moieties of the compound (e.g., the first and / or second moieties) can be non-peptides and non-nucleic acids. Alternatively or additionally, at least a portion of the first and / or second moieties of the compound can be peptides and / or nucleic acids.

[0070] A composition (e.g., a pharmaceutical composition) comprising at least the compound can be administered to a subject, for example, to treat the condition or disease of the subject. The mode of administration can be, for example, intra-articular, oral, parenteral, intravenous, intramuscular, rectal, transdermal, subcutaneous, topical, percutaneous, sublingual, nasal, vaginal, intravesical, intraurethral, intrathecal, epidural, via the ear and / or ophthalmic administration. For example, the composition can be orally ingested (e.g., a compound that is stable in the digestive system and can be absorbed into the vascular system).

[0071] The compound can be a small molecule. The compound can be non-toxic. A small molecule is intended to be a molecule having a molecular weight of 5000 g / mol (dalton) or less, for example, 2500 g / mol (dalton) or less, for example, 1000 g / mol (dalton) or less, for example, 500 g / mol (dalton) or less. In some cases, the CIP used in the aspects of the present disclosure has a molecular weight in the range of 250 to 1500 g / mol, for example, 300 to 1200 g / mol.

[0072] The compound can include a plurality of moieties (e.g., a first and a second moiety) that each bind to a plurality of endogenous proteins. Within a single compound, the first moiety and the second moiety can be coupled or linked to each other 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 each other without a linker (e.g., the two moieties can be coupled to each other via a direct chemical bond between two atoms of the two moieties). For example, the compound includes two moieties having a direct chemical bond between them, and the two moieties of the compound can be such that they form two faces (or two surfaces) of the compound that each bind to its respective protein.

[0073] The compound may include a plurality of moieties that each bind to a different endogenous protein. For example, the compound may include at least about 2 or up to about 2 moieties, at least about 3 or up to about 3 moieties, at least about 4 or up to about 4 moieties, at least about 5 or up to about 5 moieties, at least about 6 or up to about 6 moieties, at least about 7 or up to about 7 moieties, at least about 8 or up to about 8 moieties, at least about 9 or up to about 9 moieties, or at least about 10 or up to about 10 moieties. The compound may bind to at least 2 or up to 2 endogenous proteins, at least 3 or up to 3 endogenous proteins, at least 4 or up to 4 endogenous proteins, at least 5 or up to 5 endogenous proteins, at least 6 or up to 6 endogenous proteins, at least 7 or up to 7 endogenous proteins, at least 8 or up to 8 endogenous proteins, at least 9 or up to 9 endogenous proteins, or at least 10 or up to 10 endogenous proteins to form a complex. In some cases, at least one endogenous protein may be a wild-type protein or a mutant protein, and the mutant protein includes one or more amino acid mutations (e.g., one or more point mutations, one or more amino acid insertions, one or more amino acid deletions, one or more amino acid transpositions, etc.) such that the mutant protein exhibits a function or activity different from that of the wild-type protein. For example, the mutant protein may be a disease-causing protein, e.g., a mutant protein whose activity promotes the survival, proliferation, and / or spread of diseased cells (e.g., cancer cells). In some cases, the protein may be one expressed by a wild-type gene, or one expressed by a mutant gene, or a mutant protein resulting from a fusion transcript (e.g., due to chromosomal rearrangement, transcriptional error in splicing, inversion, interchromosomal or intrachromosomal translocation, chromothripsis, etc.).

[0074] In some cases, the first endogenous protein is a protein that binds to the target gene or a region near the target gene, such as a promoter or regulatory region. The first endogenous protein can bind to the target gene or a region near the target gene in the absence of the compound. In some cases, the binding of the first endogenous protein to the target gene (or region near the target gene) can be a direct binding. In other cases, the binding of the first endogenous protein to the target gene (or region near the target gene) can be an indirect binding, for example, by binding to one or more cofactors, and the cofactor(s) binds directly to the target gene. The first endogenous protein can bind to one part of the compound to form a ternary complex with the compound and the second endogenous protein. In such a scenario, the first endogenous protein (within the ternary complex) binds to the target gene or a region near the target gene and can bring the second endogenous protein in close proximity to the target gene or a region near the target gene. In some embodiments, since the first endogenous protein anchors the ternary complex to the target gene, the first endogenous protein can perform the function of an "anchor protein", specifically, when the first endogenous protein is a transcription factor, it can perform the function of an "anchor transcription factor". In some cases, the first endogenous protein can regulate the expression of the target gene in the absence of the compound. For example, the first endogenous protein can enhance the expression of the target gene in the absence of the compound, or can reduce or inhibit the expression of the target gene. In other examples, the first endogenous protein may have no effect on the expression of the target gene (for example, the first endogenous protein can bind to the target gene (or region near the target gene) but has no effect on the expression of the target gene). The first endogenous protein can be any protein that can bind (e.g., directly or indirectly) to the target gene or a region near the target gene, regardless of whether the first endogenous protein has any effect on the expression of the target gene.In some cases, the first endogenous protein may be a transcriptional modulator, such as a transcription factor, transcriptional activator, transcriptional repressor and / or epigenetic modulator and / or a signaling intermediate, which may be, but is not limited to, a kinase or phosphatase.

[0075] The first endogenous protein can bind to the coding sequence (or a portion of the coding sequence) of the target gene (e.g., directly or indirectly). Alternatively or additionally, the first endogenous protein can bind to the non-coding sequence of the target gene, such as the regulatory region of the coding sequence, such as an enhancer sequence, a promoter sequence, a CCAAT box, a TATA box, etc. (e.g., directly or indirectly). Alternatively or additionally, the first endogenous protein can bind to a sequence near the coding sequence of the target gene (e.g., directly or indirectly).For example, the first endogenous protein may bind to a sequence of at least about 1 or up to about 1 nucleic acid base, at least about 2 or up to about 2 nucleic acid bases, at least about 5 or up to about 5 nucleic acid bases, at least about 10 or up to about 10 nucleic acid bases, at least about 15 or up to about 15 nucleic acid bases, at least about 20 or up to about 20 nucleic acid bases, at least about 30 or up to about 30 nucleic acid bases, at least about 40 or up to about 40 nucleic acid bases, at least about 50 or up to about 50 nucleic acid bases, at least about 100 or up to about 100 nucleic acid bases, at least about 200 or up to about 200 nucleic acid bases, at least about 300 or up to about 300 nucleic acid bases, at least about 400 or up to about 400 nucleic acid bases, at least about 500 or up to about 500 nucleic acid bases, at least about 1,000 or up to about 1,000 nucleic acid bases, at least about 2,000 or up to about 2,000 nucleic acid bases, at least about 3,000 or up to about 3,000 nucleic acid bases, at least about 4,000 or up to about 4,000 nucleic acid bases, at least about 5,000 or up to about 5,000 nucleic acid bases, at least about 6,000 or up to about 6,000 nucleic acid bases, at least about 7,000 or up to about 7,000 nucleic acid bases, at least about 8,000 or up to about 8,000 nucleic acid bases, at least about 9,000 or up to about 9,000 nucleic acid bases, at least about 10,000 or up to about 10,000 nucleic acid bases, at least about 11,000 or up to about 11,000 nucleic acid bases, at least about 12,000 or up to about 12,000 nucleic acid bases, at least about 13,000 or up to about 13,000 nucleic acid bases, at least about 14,000 or up to about 14,000 nucleic acid bases, at least about 15,000 or up to about 15,000 nucleic acid bases, or at least about 20,000 or up to about 20,000 nucleic acid bases of the coding sequence of the target gene.

[0076] In some cases, the second endogenous protein has substantially no effect on the expression of the target gene in the absence of the formation of the compound or a ternary complex with the compound, but is recruited to the target gene in the presence of the compound (e.g., when forming a ternary complex with the compound and the first endogenous protein) and can regulate the expression of the target gene. In some cases, the second endogenous protein is a transcription regulator as described herein, such as a transcription factor, a transcriptional activator, a transcriptional repressor, and / or an epigenetic regulator and / or a signaling intermediate, such as, but not limited to, a kinase or a phosphatase. In some cases, the second endogenous protein can be a cofactor of a transcription regulator, such as a component of a mediator complex that assists the transcription regulator. An epigenetic regulator can be a protein or domain that brings about epigenetic modification of DNA, such as chromosomal DNA. Epigenetic modifications can include, but are not limited to, methylation and demethylation of DNA; modification of histones, such as methylation and demethylation (e.g., mono-, di-, tri-methylation), acetylation and deacetylation of histones, and ubiquitination, phosphorylation, and sumoylation of histones.

[0077] In some cases, the compound can include a first moiety, the first moiety being linked (e.g., by a covalent bond) to a second moiety, where: (i) the first moiety exhibits specific binding to a first endogenous protein that binds to a region near the target gene or the target gene (e.g., a promoter, a regulatory region, etc.); (ii) the second moiety exhibits specific binding to a second endogenous protein that is different from the first endogenous protein.

[0078] In some cases, the second endogenous protein can regulate the expression or activity level of an additional target gene that is different from the target gene of the first endogenous protein in the absence of the compound or in the absence of the formation of the ternary complex. By administering the compound (e.g., CIP or TCIP) to cells, the second endogenous protein can be recruited to form a ternary complex comprising the compound, the first endogenous protein, and the second endogenous protein, and the ternary complex can bind to the target gene of the first endogenous protein as described above and modulate the expression and / or activity level of the target gene. Also, the expression of the additional target gene can be modulated by the administration of the compound. For example, when the second endogenous protein is recruited to the ternary complex away from the additional target gene, the presence (e.g., amount, concentration, probability) of the second endogenous protein at or near the additional target gene is reduced, thereby potentially impairing the modulating effect of the second endogenous protein on the expression or activity level of the additional target gene. In this example, the second endogenous protein can be recruited away from the additional target gene to the target gene and modulate the expression of the target gene. Also, in another example, the complex may be formed at or near the additional target gene to recruit the first endogenous protein to the additional target gene, and the first endogenous protein may modulate the expression or activity level of the additional target gene (e.g., the effect of the second endogenous protein on the additional target gene is partially or completely reversed prior to the formation of the complex). For example, the second endogenous protein can reduce (e.g., inhibit) the expression or activity level of the additional target gene in the absence of the compound, and in the presence of the compound (and the formation of the complex), the expression or activity level of the additional target gene can increase (e.g., because the second endogenous protein is recruited away from the additional target gene); at the same time, the expression of the target gene can then be regulated by the second endogenous protein that is part of the complex.Alternatively, treatment with the compound (e.g., CIP) and subsequent formation of the complex may not result in modulation of the expression or activity level of the additional target gene of the second endogenous protein, or such modulation may not be necessary.

[0079] In some cases, the second endogenous protein may not be configured to regulate the expression or activity level of any target gene in the absence of the compound.

[0080] Also provided herein are compounds suitable for use in the practice of the methods provided herein.

[0081] In various aspects, a compound of formula (I) or (II): A-linker-B (I); or A-B (II) wherein: In the formula: (a) A is a first moiety that exhibits specific binding to a first endogenous protein within the cell, and the first endogenous protein binds to a target gene or a region near the target gene (e.g., a promoter, a regulatory region); (b) B is a second moiety that exhibits specific binding to a second endogenous protein within the cell that is different from the first endogenous protein; (c) the compound spatially forms a complex with the first endogenous protein and the second endogenous protein to confer a gain of function in the cell, Here, there is provided a compound, wherein the gain of function modulates the expression of a target gene in a manner dependent on the presence of a second endogenous protein bound to the compound. In some cases, the gain of function is achieved by utilizing less than about 50% of the amount of the second endogenous protein present in the cell. In some cases, the compound mediates the gain of function with an EC50 of less than about 1 micromolar. In some cases, the first endogenous protein reduces the expression of a target gene in the absence of the compound, the second endogenous protein enhances the expression of a further target gene in the absence of the compound, and the gain of function is characterized by (iii(a)) the expression of the certain target gene being enhanced compared to the absence of the compound, and (iii(b)) the expression of the further target gene being reduced compared to the absence of the compound. In some cases, the expression of the target gene is regulated in less than about 16 hours or about 16 hours.

[0082] In some cases, the linker is any linker as described herein. In some cases, the linker is absent, such that part A and part B are directly linked to each other (for example, the compound of formula (II)).

[0083] The terms "specific binding", "binds specifically", etc. indicate the ability of the first and second ligands or moieties to preferentially bind directly to their corresponding first and second endogenous proteins compared to other molecules or moieties within the cell. In some particular embodiments, when a given ligand or moiety and its corresponding endogenous protein are specifically bound to each other to form a binding complex, their affinity is 10 -5 M or less, 10 -6 M or less, 10 -7 M or less, 10 -8 M or less, 10 -9 M or less, 10 -10 M or less, 10 -11 M or less, 10 -12 M or less, 10 -13 M or less, 10 -14 M or less or 10 -15Characterized by a KD (dissociation constant) of less than M (note that these values may also apply to the interactions of other specific binding pairs described elsewhere in this description in some specific embodiments). The first part, the second part, and the linker that can be used in the embodiments of the present disclosure are further described in more detail below. When the compound (e.g., CIP) is supplied into the cell, for example, by contacting the cell, the first endogenous protein and the second endogenous protein spatially pair with each other via the compound (e.g., spatially form a complex), resulting in a gain of function in the cell, for example, as described in more detail below.

[0084] Compounds such as those provided herein (e.g., proximity chemical inducers or "CIPs") bind to multiple different proteins (e.g., multiple different endogenous proteins), spatially complexing (or forming a complex with) the multiple different proteins, thereby resulting in a gain of function that would not normally occur in the cell in the absence of the compound. The term "gain of function," as used herein, indicates that in the presence of the compound, which can result in the formation of a ternary complex formed by a first endogenous protein, a second endogenous protein, and a compound of the present disclosure (e.g., CIP), a certain function is realized, and the gain of function is something that would not normally be realized in the absence of the compound. If either the first endogenous protein or the second endogenous protein is not expressed intracellularly, the ternary complex cannot be formed and the gain of function is not realized. A non-limiting example of a gain of function, as used herein, is the use of a compound provided herein to recruit a second endogenous protein to a target gene such that the second endogenous protein can modulate the expression of the target gene in the presence of the compound, which is a function that 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 level of the target gene. In some other embodiments, the second endogenous protein modulates the target gene in a manner opposite to that effected by the compounds disclosed herein. In some other embodiments, the second endogenous protein can be an endogenous cancer driver, which is recruited to a target pro-apoptotic gene by a ternary complex formed by this endogenous cancer driver, a first endogenous protein that binds to the target pro-apoptotic gene, and the compound, resulting in enhanced expression of the pro-apoptotic gene.The number of different proteins bound by the compound to form the ternary complex can be at least about 2 or up to about 2 different proteins, at least about 3 or up to about 3 different proteins, at least about 4 or up to about 4 different proteins, at least about 5 or up to about 5 different proteins, at least about 6 or up to about 6 different proteins, at least about 7 or up to about 7 different proteins, at least about 8 or up to about 8 different proteins, at least about 9 or up to about 9 different proteins, at least about 10 or up to about 10 different proteins, at least about 15 or up to about 15 different proteins, or at least about 20 or up to about 20 different proteins. The plurality of different proteins can be different proteins that exhibit different activities (e.g., intrinsic or natural activities) within the cell, e.g., but not limited to, different proteins that bind to and regulate different genes within the cell.

[0085] Conventional pharmaceutical development involves the identification of a target and then the construction of methods for inhibiting, degrading, or removing the RNA or gene encoding the target. This conventional pharmaceutical development means then requires that the target be mostly removed. In contrast, in the gain-of-function approach described herein, only a small part of the target is used to confer a new therapeutic function on the cell. Advantageously, the gain-of-function described herein does not require the recruitment of all second endogenous proteins present within the cell. In some cases, all that needs to be recruited to the target gene to achieve gain-of-function is a very small percentage of the second endogenous proteins present within the cell. Without wishing to be bound by any particular theory, by using a small amount of the second endogenous protein, the subject composition is more effective over a wider therapeutic concentration range compared to other conventional therapeutic agents that require high bioavailability or high exposure to be effective.In some cases, gain of function is achieved by mobilization of less than about 50% or about 50%, less than about 45% or about 45%, less than about 40% or about 40%, less than about 35% or about 35%, less than about 30% or about 30%, less than about 25% or about 25%, less than about 20% or about 20%, less than about 15% or about 15%, less than about 10% or about 10%, less than about 9% or about 9%, less than about 8% or about 8%, less than about 7% or about 7%, less than about 6% or about 6%, less than about 5% or about 5%, less than about 4% or about 4%, less than about 3% or about 3%, less than about 2% or about 2% or less than about 1% or about 1% of the amount of a second endogenous protein present in the cell to the target gene, or by utilization of less than about 50% or about 50%, less than about 45% or about 45%, less than about 40% or about 40%, less than about 35% or about 35%, less than about 30% or about 30%, less than about 25% or about 25%, less than about 20% or about 20%, less than about 15% or about 15%, less than about 10% or about 10%, less than about 9% or about 9%, less than about 8% or about 8%, less than about 7% or about 7%, less than about 6% or about 6%, less than about 5% or about 5%, less than about 4% or about 4%, less than about 3% or about 3%, less than about 2% or about 2% or less than about 1% or about 1% of the amount of a second endogenous protein present in the cell (e.g., regulation of a target gene by a second endogenous protein in the presence of the compound, which would not normally be regulatable by the second endogenous protein in the absence of the compound).

[0086] In some cases, gain of function can be achieved by less than about 50% or about 50% of the amount of a second endogenous protein present in the cell being mobilized to the target gene, or by less than about 50% or about 50% of the amount of a second endogenous protein present in the cell being utilized (e.g., regulation of the target gene by the second endogenous protein in the presence of the compound, which would not normally be regulatable by the second endogenous protein in the absence of the compound). In some cases, gain of function can be achieved by less than about 10% or about 10% of the amount of a second endogenous protein present in the cell being mobilized to the target gene, or by less than about 10% or about 10% of the amount of a second endogenous protein present in the cell being utilized. In some instances, gain of function can be achieved by about 1% to about 30%, about 1% to about 20%, about 1% to about 15% or about 1% to about 10% of the amount of a second endogenous protein present in the cell being mobilized to the target gene, or by about 1% to about 30%, about 1% to about 20%, about 1% to about 15% or about 1% to about 10% of the amount of a second endogenous protein present in the cell being utilized. In some cases, gain of function can be achieved by about 2% to about 20% of the amount of a second endogenous protein present in the cell being mobilized to the target gene, or by about 2% to about 20% of the amount of a second endogenous protein present in the cell being utilized. In some cases, gain of function can be achieved by about 2% to about 10% of the amount of a second endogenous protein present in the cell being mobilized to the target gene, or by about 2% to about 10% of the amount of a second endogenous protein present in the cell being utilized.

[0087] In some cases, gain of function can be achieved by utilizing at least about 1% or up to about 1%, at least about 2% or up to about 2%, at least about 3% or up to about 3%, at least about 4% or up to about 4%, at least about 5% or up to about 5%, at least about 6% or up to about 6%, at least about 7% or up to about 7%, at least about 8% or up to about 8%, at least about 9% or up to about 9%, at least about 10% or up to about 10%, at least about 15% or up to about 15%, at least about 20% or up to about 20%, at least about 25% or up to about 25%, at least about 30% or up to about 30%, at least about 35% or up to about 35%, at least about 40% or up to about 40%, at least about 45% or up to about 45%, at least about 50% or up to about 50%, at least about 55% or up to about 55%, at least about 60% or up to about 60%, at least about 65% or up to about 65%, at least about 70% or up to about 70%, at least about 75% or up to about 75%, at least about 80% or up to about 80%, at least about 85% or up to about 85%, at least about 90% or up to about 90%, at least about 95% 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 and / or the second endogenous protein present within the cell.

[0088] The amount of the first endogenous protein and / or the second endogenous protein required to effectuate a gain of function as provided herein can be ascertained by a variety of methods, such as, for example, (i) chromatin immunoprecipitation (ChIP) sequencing, where the amount of the first endogenous protein that is spatially associated (e.g., bound) with the target gene of the second protein and / or (ii) the amount of the second endogenous protein that is spatially associated (e.g., bound) with the target gene of the first protein is known. Such information can be utilized together with the total amount of the first endogenous protein and / or the second endogenous protein to determine the ratio (e.g., percentage) of the first endogenous protein and / or the second endogenous protein required to effectuate a gain of function.

[0089] Compounds as provided herein (e.g., proximity chemical inducers or “CIPs”) bind to multiple different proteins (e.g., multiple different endogenous proteins), spatially complex the multiple different proteins (or form a complex with the multiple different proteins), and can result in a gain of function in the cell. The gain of function can be characterized by the induction or promotion of a cell trait (which would not normally be achieved in the absence of the compound). Non-limiting examples of such cell traits include cell death (inducing cell death, for example, within about 5 days, within about 4 days, within about 3 days, within about 2 days, within about 1 day, within about 18 hours, within about 12 hours, within about 8 hours after contacting the cell with the compound, compared to in the absence of the compound), cell survival (improving cell survival, for example, for at least about 12 hours, at least about 18 hours, at least about 1 day, at least about 2 days, at least about 7 days, at least about 2 weeks, at least about 4 weeks after contacting the cell with the compound, compared to in the absence of the compound), cell proliferation (enhancing cell proliferation, for example, 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% compared to in the absence of the compound), enhancing the expression or activity level of a target gene (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. compared to in the absence of the compound), reducing the expression or activity level of a target gene (by at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or substantially about 100% compared to in the absence of the compound).

[0090] In some cases, the compound can mediate a gain of function at an EC50 of less than about 10 micromolar or about 10 micromolar, less than about 5 micromolar or about 5 micromolar, less than about 2 micromolar or about 2 micromolar, less than about 1 micromolar or about 1 micromolar, less than about 900 nanomolar or about 900 nanomolar, less than about 800 nanomolar or about 800 nanomolar, less than about 700 nanomolar or about 700 nanomolar, less than about 600 nanomolar or about 600 nanomolar, less than about 500 nanomolar or about 500 nanomolar, less than about 400 nanomolar or about 400 nanomolar, less than about 300 nanomolar or about 300 nanomolar, less than about 200 nanomolar or about 200 nanomolar, less than about 100 nanomolar or about 100 nanomolar, less than about 90 nanomolar or about 90 nanomolar, less than about 80 nanomolar or about 80 nanomolar, less than about 70 nanomolar or about 70 nanomolar, less than about 60 nanomolar or about 60 nanomolar, less than about 50 nanomolar or about 50 nanomolar, less than about 40 nanomolar or about 40 nanomolar, less than about 30 nanomolar or about 30 nanomolar, less than about 20 nanomolar or about 20 nanomolar, less than about 10 nanomolar or about 10 nanomolar, less than about 9 nanomolar or about 9 nanomolar, less than about 8 nanomolar or about 8 nanomolar, less than about 7 nanomolar or about 7 nanomolar, less than about 6 nanomolar or about 6 nanomolar, less than about 5 nanomolar or about 5 nanomolar, less than about 4 nanomolar or about 4 nanomolar, less than about 3 nanomolar or about 3 nanomolar, less than about 2 nanomolar or about 2 nanomolar, less than about 1 nanomolar or about 1 nanomolar, less than about 0.9 nanomolar or about 0.9 nanomolar, less than about 0.8 nanomolar or about 0.8 nanomolar, less than about 0.7 nanomolar or about 0.7 nanomolar, less than about 0.6 nanomolar or about 0.6 nanomolar, less than about 0.5 nanomolar or about 0.5 nanomolar, less than about 0.4 nanomolar or about 0.4 nanomolar, less than about 0.3 nanomolar or about 0.3 nanomolar, less than about 0.2 nanomolar or about 0.2 nanomolar or less than about 0.1 nanomolar or about 0.1 nanomolar (e.g., to induce cell characteristics). In one example, the compound can mediate a gain of function at an EC50 of less than about 1 micromolar or about 1 micromolar.In another example, the compound may mediate gain of function with an EC50 of less than about 500 nanomolar or about 500 nanomolar. In another example, the compound may mediate gain of function with an EC50 of less than about 200 nanomolar or about 200 nanomolar. In another example, the compound may mediate gain of function with an EC50 of less than about 100 nanomolar or about 100 nanomolar. In another example, the compound may mediate gain of function with an EC50 of less than about 50 nanomolar or about 50 nanomolar. In another example, the compound may mediate gain of function with an EC50 of less than about 20 nanomolar or about 20 nanomolar. The term "EC50", as used herein in the context of in vitro or in vivo assays, generally refers to the concentration of a test moiety (e.g., a compound as described herein, e.g., a small molecule) at which a response (e.g., a desired response or a target response) that is about 50% of the maximum response (i.e., midway between the maximum response in the absence of the test moiety and the baseline) is induced.

[0091] In some cases, gain of function may be characterized by inhibiting the cell properties as provided herein. Thus, the compound may mediate gain of function with an IC50 of less than about 10 micromolar or about 10 micromolar, less than about 5 micromolar or about 5 micromolar, less than about 2 micromolar or about 2 micromolar, less than about 1 micromolar or about 1 micromolar, less than about 900 nanomolar or about 900 nanomolar, less than about 800 nanomolar or about 800 nanomolar, less than about 700 nanomolar or about 700 nanomolar, less than about 600 nanomolar or about 600 nanomolar, less than about 500 nanomolar or about 500 nanomolar, less than about 400 nanomolar or about 400 nanomolar, less than about 300 nanomolar or about 300 nanomolar, less than about 200 nanomolar or about 200 nanomolar, less than about 100 nanomolar or about 100 nanomolar, less than about 90 nanomolar or about 90 nanomolar, less than about 80 nanomolar or about 80 nanomolar, less than about 70 nanomolar or about 70 nanomolar, less than about 60 nanomolar or about 60 nanomolar, less than about 50 nanomolar or about 50 nanomolar, less than about 40 nanomolar or about 40 nanomolar, less than about 30 nanomolar or about 30 nanomolar, less than about 20 nanomolar or about 20 nanomolar, less than about 10 nanomolar or about 10 nanomolar, less than about 9 nanomolar or about 9 nanomolar, less than about 8 nanomolar or about 8 nanomolar, less than about 7 nanomolar or about 7 nanomolar, less than about 6 nanomolar or about 6 nanomolar, less than about 5 nanomolar or about 5 nanomolar, less than about 4 nanomolar or about 4 nanomolar, less than about 3 nanomolar or about 3 nanomolar, less than about 2 nanomolar or about 2 nanomolar, less than about 1 nanomolar or about 1 nanomolar, less than about 0.9 nanomolar or about 0.9 nanomolar, less than about 0.8 nanomolar or about 0.8 nanomolar, less than about 0.7 nanomolar or about 0.7 nanomolar, less than about 0.6 nanomolar or about 0.6 nanomolar, less than about 0.5 nanomolar or about 0.5 nanomolar, less than about 0.4 nanomolar or about 0.4 nanomolar, less than about 0.3 nanomolar or about 0.3 nanomolar, less than about 0.2 nanomolar or about 0.2 nanomolar or less than about 0.1 nanomolar or about 0.1 nanomolar (e.g., for inhibiting cell properties).As used herein in the context of in vitro or in vivo assays, the term "IC50" generally refers to the concentration of a test moiety (e.g., a compound as described herein, e.g., a small molecule) at which a response (e.g., a desired or target response) is reduced to about 50% of the maximum response in the absence of the test moiety.

[0092] Compounds such as those provided herein (e.g., proximity chemical inducers or "CIPs") bind to multiple different proteins (e.g., multiple different endogenous proteins), spatially complex the multiple different proteins (or form a complex with the multiple different proteins), and can result in a gain of function in the cell. The gain of function can be characterized in that the expression or activity level of a target gene is modulated (e.g., enhanced or reduced) by a second endogenous protein that does not substantially affect the expression or activity level of the target gene in the absence of the compound. In some cases, the gain of function is such that the expression or activity level of the target gene is at least about 1% or up to about 1%, at least about 2% or up to about 2%, at least about 5% or up to about 5%, at least about 10% or up to about 10%, at least about 15% or up to about 15%, at least about 20% or up to about 20%, at least about 30% or up to about 30%, at least about 40% or up to about 40%, at least about 50% or up to about 50%, at least about 60% or up to about 60%, at least about 70% or up to about 70%, at least about 80% or up to about 80%, at least about 90% or up to about 90%, at least about 100% or up to about 100%, at least about 150% or up to about 150%, at least about 200% or up to about 200%, at least about 300% or up to about 300%, at least about 400% or up to about 400%, at least about 500% or up to about 500%, at least about 0.1-fold or up to about 0.1-fold, at least about 0.5-fold or up to about 0.Enhanced by up to 5-fold, at least about 1-fold or up to about 1-fold, at least about 2-fold or up to about 2-fold, at least about 3-fold or up to about 3-fold, at least about 4-fold or up to about 4-fold, at least about 5-fold or up to about 5-fold, at least about 10-fold or up to about 10-fold, at least about 15-fold or up to about 15-fold, at least about 20-fold or up to about 20-fold, at least about 30-fold or up to about 30-fold, at least about 40-fold or up to about 40-fold, at least about 50-fold or up to about 50-fold, at least about 60-fold or up to about 60-fold, at least about 70-fold or up to about 70-fold, at least about 80-fold or up to about 80-fold, at least about 90-fold or up to about 90-fold, at least about 100-fold or up to about 100-fold, at least about 110-fold or up to about 110-fold, at least about 120-fold or up to about 120-fold, at least about 130-fold or up to about 130-fold, at least about 140-fold or up to about 140-fold, at least about 150-fold or up to about 150-fold, at least about 200-fold or up to about 200-fold or up to at least about 500-fold or up to about 500-fold. In some cases, the gain of function is such that the expression or activity level of the target gene is at least about 1% or up to about 1%, at least about 2% or up to about 2%, at least about 5% or up to about 5%, at least about 10% or up to about 10%, at least about 15% or up to about 15%, at least about 20% or up to about 20%, at least about 30% or up to about 30%, at least about 40% or up to about 40%, at least about 50% or up to about 50%, at least about 60% or up to about 60%, at least about 70% or up to about 70%, at least about 80% or up to about 80%, at least about 90% or up to about 90%, at least about 100% or up to about 100%, at least about 0.1-fold or up to about 0.1-fold, at least about 0.5-fold or up to about 0.It may be characterized by being reduced by up to 5-fold, at least about 1-fold or up to about 1-fold, at least about 2-fold or up to about 2-fold, at least about 3-fold or up to about 3-fold, at least about 4-fold or up to about 4-fold, at least about 5-fold or up to about 5-fold, at least about 10-fold or up to about 10-fold, at least about 15-fold or up to about 15-fold, at least about 20-fold or up to about 20-fold, at least about 30-fold or up to about 30-fold, at least about 40-fold or up to about 40-fold, at least about 50-fold or up to about 50-fold, at least about 60-fold or up to about 60-fold, at least about 70-fold or up to about 70-fold, at least about 80-fold or up to about 80-fold, at least about 90-fold or up to about 90-fold, or at least about 100-fold or up to about 100-fold.

[0093] In some cases, the compound may include a plurality of different moieties that exhibit specific binding to a plurality of different endogenous proteins. The plurality of different endogenous proteins may include (i) a first endogenous protein that results in a reduction (or enhancement) in the expression of a first target gene and (ii) a second endogenous protein that results in an enhancement (or reduction) in the expression of a second target gene. In such scenarios, the gain of function achieved by the compound may be characterized by a change (e.g., inversion, or induction of the opposite effect) in the expression profile of the first target gene and / or the second target gene.

[0094] In some cases, gain of function is (1) the expression of the first target gene is at least about 1% or up to about 1%, at least about 2% or up to about 2%, at least about 5% or up to about 5%, at least about 10% or up to about 10%, at least about 15% or up to about 15%, at least about 20% or up to about 20%, at least about 30% or up to about 30%, at least about 40% or up to about 40%, at least about 50% or up to about 50%, at least about 60% or up to about 60%, at least about 70% or up to about 70%, at least about 80% or up to about 80%, at least about 90% or up to about 90%, at least about 100% or up to about 100%, at least about 150% or up to about 150%, at least about 200% or up to about 200%, at least about 300% or up to about 300%, at least about 400% or up to about 400%, at least about 500% or up to about 500%, at least about 0.1-fold or up to about 0.1-fold, at least about 0.5-fold or up to about 0.Enhanced by up to 5-fold, at least about 1-fold or up to about 1-fold, at least about 2-fold or up to about 2-fold, at least about 3-fold or up to about 3-fold, at least about 4-fold or up to about 4-fold, at least about 5-fold or up to about 5-fold, at least about 10-fold or up to about 10-fold, at least about 15-fold or up to about 15-fold, at least about 20-fold or up to about 20-fold, at least about 30-fold or up to about 30-fold, at least about 40-fold or up to about 40-fold, at least about 50-fold or up to about 50-fold, at least about 60-fold or up to about 60-fold, at least about 70-fold or up to about 70-fold, at least about 80-fold or up to about 80-fold, at least about 90-fold or up to about 90-fold, at least about 100-fold or up to about 100-fold, at least about 110-fold or up to about 110-fold, at least about 120-fold or up to about 120-fold, at least about 130-fold or up to about 130-fold, at least about 140-fold or up to about 140-fold, at least about 150-fold or up to about 150-fold, at least about 200-fold or up to about 200-fold or up to at least about 500-fold or up to about 500-fold, and / or (2) the expression of the second target gene is at least about 1% or up to about 1%, at least about 2% or up to about 2%, at least about 5% or up to about 5%, at least about 10% or up to about 10%, at least about 15% or up to about 15%, at least about 20% or up to about 20%, at least about 30% or up to about 30%, at least about 40% or up to about 40%, at least about 50% or up to about 50%, at least about 60% or up to about 60%, at least about 70% or up to about 70%, at least about 80% or up to about 80%, at least about 90% or up to about 90%, at least about 95% or up to about 95%, substantially about 100%, at least about 0.1-fold or up to about 0.1-fold, at least about 0.5-fold or up to about 0.Reduced by up to 5-fold, at least about 1-fold or up to about 1-fold, at least about 2-fold or up to about 2-fold, at least about 3-fold or up to about 3-fold, at least about 4-fold or up to about 4-fold, at least about 5-fold or up to about 5-fold, at least about 10-fold or up to about 10-fold, at least about 15-fold or up to about 15-fold, at least about 20-fold or up to about 20-fold, at least about 30-fold or up to about 30-fold, at least about 40-fold or up to about 40-fold, at least about 50-fold or up to about 50-fold, at least about 60-fold or up to about 60-fold, at least about 70-fold or up to about 70-fold, at least about 80-fold or up to about 80-fold, at least about 90-fold or up to about 90-fold, or at least about 100-fold or up to about 100-fold, and may be characterized thereby.

[0095] Conversely, for gain-of-function, (1) the expression of the first target gene is reduced to at least about 1% or up to about 1%, at least about 2% or up to about 2%, at least about 5% or up to about 5%, at least about 10% or up to about 10%, at least about 15% or up to about 15%, at least about 20% or up to about 20%, at least about 30% or up to about 30%, at least about 40% or up to about 40%, at least about 50% or up to about 50%, at least about 60% or up to about 60%, at least about 70% or up to about 70%, at least about 80% or up to about 80%, at least about 90% or up to about 90%, at least about 100% or up to about 100%, at least about 150% or up to about 150%, at least about 200% or up to about 200%, at least about 300% or up to about 300%, at least about 400% or up to about 400%, at least about 500% or up to about 500%, at least about 0.1-fold or up to about 0.1-fold, at least about 0.5-fold or up to about 0.Reduced by up to 5-fold, at least about 1-fold or up to about 1-fold, at least about 2-fold or up to about 2-fold, at least about 3-fold or up to about 3-fold, at least about 4-fold or up to about 4-fold, at least about 5-fold or up to about 5-fold, at least about 10-fold or up to about 10-fold, at least about 15-fold or up to about 15-fold, at least about 20-fold or up to about 20-fold, at least about 30-fold or up to about 30-fold, at least about 40-fold or up to about 40-fold, at least about 50-fold or up to about 50-fold, at least about 60-fold or up to about 60-fold, at least about 70-fold or up to about 70-fold, at least about 80-fold or up to about 80-fold, at least about 90-fold or up to about 90-fold, at least about 100-fold or up to about 100-fold, at least about 110-fold or up to about 110-fold, at least about 120-fold or up to about 120-fold, at least about 130-fold or up to about 130-fold, at least about 140-fold or up to about 140-fold, at least about 150-fold or up to about 150-fold, at least about 200-fold or up to about 200-fold or up to at least about 500-fold or up to about 500-fold, and / or (2) the expression of the second target gene is at least about 1% or up to about 1%, at least about 2% or up to about 2%, at least about 5% or up to about 5%, at least about 10% or up to about 10%, at least about 15% or up to about 15%, at least about 20% or up to about 20%, at least about 30% or up to about 30%, at least about 40% or up to about 40%, at least about 50% or up to about 50%, at least about 60% or up to about 60%, at least about 70% or up to about 70%, at least about 80% or up to about 80%, at least about 90% or up to about 90%, at least about 95% or up to about 95%, substantially about 100%, at least about 0.1-fold or up to about 0.1-fold, at least about 0.5-fold or up to about 0.Up to 5 times, at least about 1 time or up to about 1 time, at least about 2 times or up to about 2 times, at least about 3 times or up to about 3 times, at least about 4 times or up to about 4 times, at least about 5 times or up to about 5 times, at least about 10 times or up to about 10 times, at least about 15 times or up to about 15 times, at least about 20 times or up to about 20 times, at least about 30 times or up to about 30 times, at least about 40 times or up to about 40 times, at least about 50 times or up to about 50 times, at least about 60 times or up to about 60 times, at least about 70 times or up to about 70 times, at least about 80 times or up to about 80 times, at least about 90 times or up to about 90 times or at least about 100 times or up to about 100 times may be characterized by being enhanced.

[0096] In some cases, the functional gains achieved by the compositions, systems, and methods provided herein may be characterized by modulating (e.g., enhancing or reducing) the expression or activity level of a target gene (e.g., by a second endogenous protein in the presence of the compound, where the second endogenous protein has substantially no effect on the expression or activity level of the target gene in the absence of the compound). In some other cases, the second endogenous protein modulates the target gene in a manner opposite to that effected by the compounds disclosed herein. In some cases, the expression or activity level of the target gene may be modulated (e.g., enhanced or reduced) in less than about 16 hours or about 16 hours, less than about 15 hours or about 15 hours, less than about 14 hours or about 14 hours, less than about 13 hours or about 13 hours, less than about 12 hours or about 12 hours, less than about 11 hours or about 11 hours, less than about 10 hours or about 10 hours, less than about 9 hours or about 9 hours, less than about 8 hours or about 8 hours, less than about 7 hours or about 7 hours, less than about 6 hours or about 6 hours, less than about 5 hours or about 5 hours, less than about 4 hours or about 4 hours, less than about 3 hours or about 3 hours, less than about 2 hours or about 2 hours, or less than about 1 hour or about 1 hour after contacting the cells with the compound as compared to the absence of the compound. In one example, the expression or activity level of the target gene may be modulated (e.g., enhanced or reduced) in less than about 16 hours or about 16 hours after contacting the cells with the compound as compared to the absence of the compound. In another example, the expression or activity level of the target gene may be modulated (e.g., enhanced or reduced) in less than about 8 hours or about 8 hours after contacting the cells with the compound as compared to the absence of the compound.

[0097] Any modulation of the expression level of a target gene as provided herein can be induced or observed in less than about 48 hours or about 48 hours, less than about 42 hours or about 42 hours, less than about 36 hours or about 36 hours, less than about 30 hours or about 30 hours, less than about 24 hours or about 24 hours, less than about 18 hours or about 18 hours, less than about 12 hours or about 12 hours, less than about 10 hours or about 10 hours, less than about 9 hours or about 9 hours, less than about 8 hours or about 8 hours, less than about 7 hours or about 7 hours, less than about 6 hours or about 6 hours, less than about 5 hours or about 5 hours, less than about 4 hours or about 4 hours, less than about 3 hours or about 3 hours, less than about 2 hours or about 2 hours, less than about 1 hour or about 1 hour, less than about 45 minutes or about 45 minutes, less than about 30 minutes or about 30 minutes, less than about 20 minutes or about 20 minutes, less than about 15 minutes or about 15 minutes or less than about 10 minutes or about 10 minutes (e.g., by experimental techniques).

[0098] The first endogenous protein, the second endogenous protein, or both, may confer or exhibit activity in cells in the absence and / or presence of the compound. Non-limiting examples of such activities include transcriptional activation activity, transcriptional repression activity, methyltransferase activity, demethylase activity, dismutase activity, alkylation activity, depurination activity, oxidation activity, pyrimidine dimer formation activity, integrase activity, transposase activity, recombinase activity, polymerase activity, ligase activity, helicase activity, photolyase activity or glycosylase activity, acetyltransferase activity, deacetylase activity, kinase activity, phosphatase activity, ubiquitin ligase activity, deubiquitination activity, adenylation activity, deadenylation activity, SUMOylation activity, desumoylation activity, ribosylation activity, deribosylation activity, myristoylation activity, remodeling activity, protease activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, synthase activity, synthetase activity, and / or demyristoylation activity, and one or more members thereof may be mentioned. The first endogenous protein, the second endogenous protein, or both, may exhibit such activity in the absence of the compound (e.g., proximity chemical inducer or "CIP"). Alternatively or additionally, the first endogenous protein, the second endogenous protein, or both, may confer or exhibit such activity in the presence of the compound.When bound to the compound, the first endogenous protein, the second endogenous protein, or both may exhibit at least about 1% or up to about 1%, at least about 2% or up to about 2%, at least about 5% or up to about 5%, at least about 10% or up to about 10%, at least about 15% or up to about 15%, at least about 20% or up to about 20%, at least about 25% or up to about 25%, at least about 30% or up to about 30%, at least about 40% or up to about 40%, at least about 50% or up to about 50%, at least about 60% or up to about 60%, at least about 70% or up to about 70%, at least about 80% or up to about 80%, at least about 90% or up to about 90%, at least about 95% or up to about 95%, or substantially about 100% of the activity they exhibit in the absence of the compound.

[0099] The first endogenous protein, the second endogenous protein, or both (e.g., forming a ternary complex with the compound) can be any protein of interest having any desired activity. Non-limiting examples of the first endogenous protein and / or the second endogenous protein include secreted proteins, non-secreted proteins, chaperone proteins, transposases, integrases, recombinases, resolvases, invertases, proteases, helicases, methyltransferases, demethylases, acetylases, deacetylases, phosphatases, kinases, nucleases, transcriptional repressors, transcriptional activators, transcriptional coactivators, transcription-protein mobilizing proteins, cell uptake activity-related proteins, nucleic acid-binding proteins, nucleic acid-forming proteins, signal peptides or signal proteins, nuclear proteins, cytoplasmic proteins or cytosolic proteins, membrane proteins (e.g., transmembrane proteins or intracellular membrane proteins), non-membrane proteins, any fragment thereof, any variant thereof, and any combination thereof. In some cases, the first endogenous protein, the second endogenous protein, or both can be transcription factors, e.g., transcriptional repressors, transcriptional activators, and / or transcriptional coactivators. In some cases, the first endogenous protein, the second endogenous protein, or both can be epigenetic modulators that exhibit enzymatic activity resulting in epigenetic modification of a target gene (e.g., DNA, e.g., chromosomal DNA). Epigenetic modifications can include, but are not limited to, methylation and demethylation of DNA, histone modifications such as methylation and demethylation (e.g., mono-, di-, and tri-methylation), acetylation and deacetylation of histones, ubiquitination of histones, phosphorylation of histones, and sumoylation of histones. In some cases, the protein as used herein can refer to the whole or a part of the protein (e.g., a fragmented part) or a functional domain of the protein. In some cases, the protein (e.g., the first and / or the second endogenous protein) is a non-viral protein (e.g., a mammalian protein).Alternatively, the protein (e.g., the first and / or second endogenous protein) can be a viral protein (e.g., one derived from a viral genome).

[0100] In some cases, the protein (e.g., the first endogenous protein and / or the second endogenous protein) bound by the compound is not a protease and / or does not affect the degradation of further proteins. For example, the first endogenous protein and the second endogenous protein can be bound by the compound to form a ternary complex, where (i) the first endogenous protein of the ternary complex does not directly or indirectly induce the degradation of the second endogenous protein, and / or (ii) the second endogenous protein of the ternary complex does not directly or indirectly induce the degradation of the first endogenous protein. Alternatively, the first endogenous protein bound in the ternary complex can be a protease and / or can cause the degradation of the second endogenous protein of the same complex.

[0101] In some cases, the protein (e.g., the first and / or second endogenous protein) that binds to the compounds as provided herein can be a functional protein that exhibits an inherent or natural function (e.g., binding to a target gene, associating with a target gene, and / or regulating the expression of a target gene) prior to, for example, forming a complex with the compound. Thus, upon forming a complex with the compound, at least a portion of such activity can be reduced (e.g., by at least about 1% or up to about 1%, at least about 2% or up to about 2%, at least about 5% or up to about 5%, at least about 10% or up to about 10%, at least about 15% or up to about 15%, at least about 20% or up to about 20%, at least about 25% or up to about 25%, at least about 30% or up to about 30%, at least about 40% or up to about 40%, at least about 50% or up to about 50%, at least about 60% or up to about 60%, at least about 70% or up to about 70%, at least about 80% or up to about 80%, at least about 90% or up to about 90%, at least about 95% or up to about 95%, or substantially about 100%).

[0102] In some cases, the first endogenous protein as provided herein can be, for example, an anchor transcription factor, and the second endogenous protein as provided herein can be, for example, a transcription modulation factor. In such scenarios, the compound can be referred to as a "TCIP".

[0103] In certain non-limiting embodiments, the first endogenous protein comprises a BTB domain. The terms "BTB domain", "BR-C, ttk and bab domain", "POZ domain" and "Pox virus and Zinc finger domain" are used interchangeably herein and generally refer to a domain (e.g., a structural domain) of a protein that mediates the multimerization of proteins (e.g., homomeric dimerization, heteromeric dimerization, etc.). Specific examples of such proteins are shown in more detail below (see, for example, the examples of proteins containing the BTB domain in Table 3).

[0104] In certain non-limiting embodiments, the second endogenous protein can be various. Examples of the second endogenous protein include, but are not limited to, BET proteins, such as BRD2, BRD3, BRD4, BRD5, BRD7, BRD9 and BRDT; intracellular receptors, hormone receptors, such as estrogen receptor, androgen receptor, kinases, phosphatases; and the like.

[0105] The first and second portions (A and B) The nature of the first and second portions of the CIP compound (also referred to herein as the first and second ligands) and the linker element (when used) can vary. In any given CIP compound, the first and second ligands are selected based on the nature of the corresponding first endogenous protein and second endogenous protein to which these portions bind. Specific examples of corresponding anchors (e.g., the first endogenous protein) and transcription modulation factors (e.g., the second endogenous protein and certain non-limiting portions of its corresponding ligand) are shown below. The specificity of activity with respect to a particular cell type can be provided by the selection of the first and second ligands of the CIP configured to mobilize the first endogenous protein and the second endogenous protein in a manner that provides the desired cell or condition specificity. For example, the CIP can be engineered to induce proximity between the first endogenous protein and the second endogenous protein that predominantly exists within the target cells of interest such that the CIP exhibits highly selective activity against those cells. The selectivity of a given CIP can be represented by the following formula: (Selectively of the expression of the first endogenous protein) × (Selectively of the expression of the second endogenous protein) × (Genomic specificity of the first endogenous protein) = Selectivity of the induced activity

[0106] Examples of the first and second portions (e.g., A and B in the formula of the compounds provided herein, also referred to herein as the first and second ligands) that can be used in various CIPs are outlined in further detail below. Suitable first and second portions that can be used in the CIPs of aspects of the present disclosure and methods for identifying them are also shown in PCT Application No. PCT / US2021 / 058231, published as WO2022 / 098989; the disclosure of which is incorporated herein by reference.

[0107] Linker As described above, the present disclosure provides a compound (e.g., CIP) having two ligands covalently linked via a linker, such as a BCL-6 (B-cell lymphoma 6) ligand and a second ligand (e.g., a BRD4 (bromodomain-containing 4) ligand, an ER ligand, an AR ligand, a CDK ligand, etc.). When used, any convenient linker for linking the first ligand and the second ligand to each other can be used. The linker of interest is a linker that results in a stable association of the first ligand and the second ligand in such a manner that the first and second ligands have the ability to specifically bind to their respective endogenous factors within the cell. Since the linker results in a stable association of the first ligand and the second ligand with each other, the first ligand and the second ligand do not dissociate from each other under cellular conditions, such as conditions at the cell surface, conditions inside the cell, etc. The linker can be provided for the stable association of the first ligand and the second ligand using any convenient bond, such as a covalent or non-covalent bond, where in some cases, the linker element is covalently bonded to both the first ligand and the second ligand. 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 via carbene intermediates, metathesis reactions among several types of bond-forming reactions.In some embodiments, reactive ligation chemistry is used for the linker, in which case, as reactive linker pairs (e.g., provided by a ligand and moieties on the linker), but not limited to, maleimide / thiol; thiol / thiol; pyridyldithiol / thiol; succinimidyl iodoacetate / thiol; N-succinimidyl ester (NHS ester), sulfodichlorophenol ester (SDP ester) or pentafluorophenyl-ester (PFP ester) / amine; bissuccinimidyl ester / amine; imido ester / amine; 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-1-carboxylate) / thiol and amine / BMPH (N-[β-maleimidopropionic acid] hydrazide.TFA) / thiol; azide / triarylphosphine; nitrone / cyclooctyne; azide / tetrazine and formylbenzamide / hydrazino-nicotinamide can be mentioned. In some specific embodiments, the linker is subjected to a cycloaddition reaction, such as a [1+2]-cycloaddition, [2+2]-cycloaddition, [3+2]-cycloaddition, [2+4]-cycloaddition, [4+6]-cycloaddition or a cheletropic reaction, such as 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 can include an alkyl chain, an alkoxy chain, an alkenyl chain or an alkynyl chain, where the number of carbon atoms in the chain can vary, and in some cases is in the range of 2 to 25, for example 5 to 20, and one or more carbon atoms are replaced by NH or CH3-N as reactive functional moieties for covalent bonds.

[0108] In some cases, the linker is selected from the group having the following, where n represents the total number of carbon atoms or carbon-substituent atoms that may be present and may be sub-counted by k, m, and / or p:

[0109] In some cases, the linker is selected from the group comprising the following, where n represents the total number of carbon atoms or carbon-substituent atoms that may be present and may be sub-counted by k, m, and / or p: a) L which is a Cn alkyl chain where one or more carbon atoms are replaced by NH or CH 3 -N including the case where it is replaced b) L which is a Cn alkoxy chain where one or more carbon atoms are replaced by NH or CH 3 -N including the case where it is replaced c) L which is a Cn alkenyl or alkenyloxy chain where one or more carbon atoms are replaced by NH or CH 3 -N including the case where it is replaced d) L which is a Cn alkynyl or alkynyloxy chain where one or more carbon atoms are replaced by NH or CH 3 -N including the case where it is replaced e) L 1 -Ar-L 2 or L 1 -Het-L 2 wherein L1 and L 2 can be a bond or either carbon or optionally substituted nitrogen, for example an alkenyl, alkynyl, alkynyloxy, alkenyloxy, alkoxy or alkyl chain of 1 to 10 atoms such as CH 2 N(H)CH 2 , CH 2 OCH 2 , C 5 H 10 OCH 2 etc.; Ar is a 6-membered optionally substituted aryl; 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.

[0110] In some embodiments, the linker comprises a C(1-16) alkyl chain. In some cases, the linker comprises a C(1-16) alkyl chain in which one or more methylene groups are replaced by NH or CH 3 -N. In some cases, the linker comprises a C(1-16) alkoxy chain. In some cases, the linker comprises a C(1-16) alkoxy chain in which one or more methylene groups are replaced by NH or CH 3 -N. In some specific cases, the linker comprises L 1 -cyclo-L 2 、L 1 -heterocyclo-L 2 、L 1 -Ar-L 2 or L 1 -Het-L 2 wherein L 1 and L 2 can be a bond, alkenyl, alkynyl, alkynyloxy, alkenyloxy, alkoxy or alkyl chain, in which case: cyclo is C(3-8) cycloalkyl or substituted C(3-8) cycloalkyl; heterocyclo is C(3-8) heterocycloalkyl or substituted C(3-8) heterocycloalkyl; Ar is an aryl group or a substituted aryl group; Het is a heteroaryl group or a substituted heteroaryl group.

[0111] In some specific embodiments, the linker is TIFF2025517099000004.tif230148 wherein m, n and p are independently selected from 0 or integers from 1 to 12 selected from.

[0112] Suitable linkers that may be used in aspects of the present disclosure are further described in International Patent Application Publication Nos. WO2020219650 and WO2017185023, as well as U.S. Patent No. 10,532,103 and U.S. Patent Application Publication No. 20190111143; the disclosures of which are incorporated herein by reference.

[0113] In some aspects, the linker of interest includes, for example, those described in International Patent Application Publication No. WO2020 / 264499, the disclosure of which is incorporated herein by reference. For example, the linker is TIFF2025517099000005.tif 188149 TIFF2025517099000006.tif 199149 TIFF2025517099000007.tif 189149 TIFF2025517099000008.tif 200150 TIFF2025517099000009.tif 184149 TIFF2025517099000010.tif 189150 TIFF2025517099000011.tif 203149 TIFF2025517099000012.tif 205149 TIFF2025517099000013.tif 202150 TIFF2025517099000014.tif 180149 TIFF2025517099000015.tif 176150 TIFF2025517099000016.tif 199150 TIFF2025517099000017.tif 197149 TIFF2025517099000018.tif 192150 TIFF2025517099000019.tif 185151 TIFF2025517099000020.tif 189150 TIFF2025517099000021.tif 204150 TIFF2025517099000022.tif 184150 TIFF2025517099000023.tif 206150 TIFF2025517099000024.tif 202150 TIFF2025517099000025.tif 199150 TIFF2025517099000026.tif 196149 TIFF2025517099000027.tif 207150 TIFF2025517099000028.tif 203150 TIFF2025517099000029.tif 204150 TIFF2025517099000030.tif 196150 TIFF2025517099000031.tif 196149 TIFF2025517099000032.tif 207155 TIFF2025517099000033.tif can be selected from 47148.

[0114] In some embodiments, linkers suitable for use in the compounds of the present disclosure (e.g., CIP, TCIP) are those shown in U.S. Patent Application Publication No. 2019 / 0076540A1, which is hereby incorporated by reference in its entirety for the disclosure of the linkers.

[0115] In some embodiments, linkers suitable for use in the compounds of the present disclosure (e.g., CIP, TCIP) are as follows: TIFF2025517099000034.tif185152TIFF2025517099000035.tif189146 may include one or more constituents selected from.

[0116] 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: TIFF2025517099000036.tif178128 wherein: X 1 and X 2 are independently a bond, NH, NR 25 、CH 2 、CHR 25 、C(R 25 ) 2 、O, and S; R 20 、R 21 、R 22 、R 23 and R 24 are independently a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -C(O)alkyl, -C(O)Oalkyl, -C(S)-, -SO 2 -, -S(O)-, -C(S)-, -C(O)NH-, -NHC(O)-, -N(alkyl)C(O)-, -C(O)N(alkyl)-, -O-, -S-, -NH-, -N(alkyl)-, -CH(-O-R 26 )-, -CH(-NHR 25 )-, -CH(-NH 2 )-, -CH(-NR 25 2 )-, -C(-O-R 26 )alkyl-, -C(-NHR25 ) alkyl-, -C(-NH 2 ) alkyl-, -C(-NR 25 2 ) alkyl-, -C(R 4 R 4 )-, -alkyl(R 27 )-alkyl(R 28 )-, -C(R 27 R 28 )-, -P(O)(OR 26 )O-, -P(O)(OR 26 )-, -NHC(O)NH-, -N(R 25 )C(O)N(R 25 )-, -N(H)C(O)N(R 25 )-, - polyethylene glycol, poly(lactic-co-glycolic acid), alkene, haloalkyl, alkoxy and alkyne; or R 20 , R 21 , R 22 , R 23 and R 24 are, in addition to the above, independently, heteroarylalkyl, aryl, arylalkyl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, polypropylene glycol, lactic acid, glycolic acid, carbocycle or -O-(CH 2 ) 1~12 -O-, -NH-(CH 2 ) 1~12 -NH-, -NH-(CH 2 ) 1~12 -O- or -O-(CH 2 ) 1~12 -NH-, -S-(CH 2 ) 1~12 -O-, -O-(CH 2 ) 1~12 -S-, -S-(CH 2 ) 1~12 -S-, -S-(CH 2 ) 1~12 -NH-, -NH-(CH 2 ) 1~12 -S- (wherein 1 to 12 can independently be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and one or more CH 2Or NH may be modified by substitution of H with, for example, methyl, ethyl, cyclopropyl, F (when on carbon), etc., and optionally heteroatoms, heteroalkyl groups, aryl groups, heteroaryl groups or cycloaliphatic groups may be interspersed in the chain), and may be selected from

[0117] As some specific non-limiting examples, -O-CH(CH 3 )-CH(CH 3 )CH-O-, -O-CH 2 -CH(CH 3 )CH-O-, -O-CH(CH 3 )-CH 2 CH-O- etc. may be mentioned, R 20 , R 21 , R 22 , R 23 and R 24 each is one or more substituents selected from R 101 or may also be substituted as described herein; R 25 in each case where it exists, is selected from alkyl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, alkenyl or alkynyl, or may also be aliphatic, heteroaliphatic, aryl, heteroaryl or heterocyclic; R 26 is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene and alkyne; or in addition to these, may be selected from aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic; R 27 and R 28 are independently selected from hydrogen, alkyl, amine, or they combine with the carbon atom to which they are attached to form C(O), C(S), C=CH 2 , C 3 ~C 6forms a 4-, 5- or 6-membered spiro heterocyclic ring containing a spiro carbon ring or one or two heteroatoms selected from N and O, or forms a bridge-bonded ring of one or two carbons; R 101 is, independently at each occurrence, hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -COO alkyl, COOH, NO 2 、F, Cl, Br, I, CF 3 、NH 2 、NH alkyl, N(alkyl) 2 、NR 25 R 25 、NHR 25 、aliphatic, heteroaliphatic and COR 4 selected from; R 4 is hydrogen, alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclic, hydroxyl, alkoxy, amine, -NH alkyl or -N alkyl 2 selected from.

[0118] In a further aspect, the linker is of formulae LVIII, LIX, and LX: TIFF2025517099000037.tif92128 wherein each variable part is as defined in formula LI selected from the group consisting of. In alternative embodiments of LVIII, LIX and LX, a carbocyclic ring is used instead of a heterocyclic ring.

[0119] The following are non-limiting examples of linkers that can be used in the present disclosure. As some specific non-limiting examples, as formula LI, formula LII, formula LIII, formula LIV, formula LV, formula LVI or formula LVII, TIFF2025517099000038.tif153128TIFF2025517099000039.tif147128TIFF2025517099000040.tif152128TIFF2025517099000041.tif123128TIFF2025517099000042.tif21091 may be mentioned.

[0120] In some embodiments, the linker may be selected from TIFF2025517099000043.tif121128.

[0121] In some embodiments, the linker may be selected from TIFF2025517099000044.tif161128TIFF2025517099000045.tif155128.

[0122] In some embodiments, X 1 may be attached to the first part and / or the second part (of the compounds of the present disclosure). In other embodiments, X 2 may be attached to the first part and / or the second part (of the compounds of the present disclosure).

[0123] Non-limiting examples of the R20, R21, R22, R23 and R24 moieties include: TIFF2025517099000046.tif178128.

[0124] R 20 、R 21 、R 22 、R 23 and R 24 Additional non-limiting examples of the moieties include TIFF2025517099000047.tif148128TIFF2025517099000048.tif137128TIFF2025517099000049.tif151128TIFF2025517099000050.tif143128.

[0125] R20 、R 21 、R 22 、R 23 and R 24 As further non-limiting examples of the TIFF2025517099000051.tif165128TIFF2025517099000052.tif161128 can be mentioned.

[0126] In some embodiments, the linker group can be a (poly)ethylene glycol which may be substituted, 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 ethylene glycol units, or an optionally substituted alkyl group in which O, N, S, P or Si atoms are interspersed. In some embodiments, the linker can be adjacent to, substituted with, or have the group interspersed with an aryl, phenyl, benzyl, alkyl, alkylene or heterocyclic group. In some embodiments, the linker can be asymmetric or symmetric. In some embodiments, the linker can be a substituted or unsubstituted polyethylene glycol group in the range of about 1 to about 12 ethylene glycol units, 1 to about 10 ethylene glycol units, about 2 to about 6 ethylene glycol units, about 2 to about 5 ethylene glycol units or about 2 to about 4 ethylene glycol units in size. In any embodiment of the compounds described herein, the linker group can be any suitable moiety as described herein.

[0127] In some embodiments, the linker is -NR 61 (CH 2 ) n1 -(lower alkyl)-, -NR 61 (CH 2 ) n1 -(lower alkoxyl)-, -NR 61 (CH 2 ) n1 -(lower alkoxyl)-OCH 2 -, -NR61 (CH 2 ) n1 -(lower alkoxyl)-(lower alkyl)-OCH 2 -、 -NR 61 (CH 2 ) n1 -(cycloalkyl)-(lower alkyl)-OCH 2 -、-NR 61 (CH 2 ) n1 -(heterocycloalkyl)-、 -NR 61 (CH 2 CH 2 O) n1 -(lower alkyl)-O-CH 2 -、-NR 61 (CH 2 CH 2 O) n1 -(heterocycloalkyl)-O-CH 2 -、 -NR 61 (CH 2 CH 2 O) n1 -aryl-O-CH 2 -、-NR 61 (CH 2 CH 2 O) n1 -(heteroaryl)-O-CH 2 -、 -NR 61 (CH 2 CH 2 O) n1 -(cycloalkyl)-O-(heteroaryl)-O-CH 2 -、 -NR 61 (CH 2 CH 2 O) n1 -(cycloalkyl)-O-aryl-O-CH 2 -、 -NR 61 (CH 2 CH 2 O) n1 -(lower alkyl)-NH-aryl-O-CH 2 -、 -NR 61(CH 2 CH 2 O) n1 -(lower alkyl)-O-aryl-CH 2 、 -NR 61 (CH 2 CH 2 O) n -cycloalkyl-O-aryl-, -NR 61 (CH 2 CH 2 O) n -cycloalkyl-O-heteroaryl-, -NR 61 (CH 2 CH 2 ) n1 -(cycloalkyl)-O-(heterocyclic ring)-CH 2 、 -NR 61 (CH 2 CH 2 ) n1 -(heterocyclic ring)-(heterocyclic ring)-CH 2 and -NR 61 -(heterocyclic ring)-CH 2 may be selected from; wherein, n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R 61 is H, methyl or ethyl.

[0128] In some embodiments, the linker is, -N(R 61 )-(CH 2 ) m1 -O(CH 2 ) n2 -O(CH 2 ) o1 -O(CH 2 ) p1 -O(CH 2 ) q1 -O(CH 2 ) r1 -OCH 2 -, -O-(CH 2 ) m1 -O(CH 2 ) n2 -O(CH2 ) o1 -O(CH 2 ) p1 -O(CH 2 ) q1 -O(CH 2 ) r1 -OCH 2 -、 -O-(CH 2 ) m1 -O(CH 2 ) n2 -O(CH 2 ) o1 -O(CH 2 ) p1 -O(CH 2 ) q1 -O(CH 2 ) r1 -O-; -N(R 61 )-(CH 2 ) m1 -O(CH 2 ) n2 -O(CH 2 ) o1 -O(CH 2 ) p1 -O(CH 2 ) q1 -O(CH 2 ) r1 -O-; -(CH 2 ) m1 -O(CH 2 ) n2 -O(CH 2 ) o1 -O(CH 2 ) p1 -O(CH 2 ) q1 -O(CH 2 ) r1 -O-; -(CH 2 ) m1 -O(CH 2 ) n2 -O(CH 2 ) o1 -O(CH 2 ) p1 -O(CH 2 ) q1 -O(CH 2 ) r1 -OCH2 -; -O(CH 2 ) m1 -O(CH 2 ) n2 O(CH 2 ) p1 O(CH 2 ) q1 OCH 2 -; -O(CH 2 ) m1 O(CH 2 ) n2 O(CH 2 ) p1 O(CH 2 ) q1 OCH 2 - may be selected from; wherein, m1, n2, o1, p1, q1 and r1 are independently 1, 2, 3, 4 or 5; R 61 is H, methyl or ethyl.

[0129] In some embodiments, the linker is, TIFF2025517099000053.tif132128TIFF2025517099000054.tif139128wherein m1, n2, o1, p1, q2 and r1 are independently 1, 2, 3, 4 or 5 may be selected from.

[0130] In some embodiments, the linker is, TIFF2025517099000055.tif138139TIFF2025517099000056.tif162128TIFF2025517099000057.tif113135TIFF2025517099000058.tif203149TIFF2025517099000059.tif174128TIFF2025517099000060.tif193130TIFF2025517099000061.tif183128TIFF2025517099000062.tif194139TIFF2025517099000063.tif193127TIFF2025517099000064.tif193130TIFF2025517099000065.tif193124TIFF2025517099000066.tif170128TIFF2025517099000067.tif193129TIFF2025517099000068.tif193123TIFF2025517099000069.tif193116TIFF2025517099000070.tif192123TIFF2025517099000071.tif191128TIFF2025517099000072.tif192134TIFF2025517099000073.tif192131TIFF2025517099000074.tif193138TIFF2025517099000075.tif185128TIFF2025517099000076.tif191133TIFF2025517099000077.tif193141TIFF2025517099000078.tif192134TIFF2025517099000079.tif189137TIFF2025517099000080.tif192141TIFF2025517099000081.tif194142Wherein, R 71 is -O-, -NH, -NMe, -N-alkyl, N-(aliphatic), -N-(heteroaliphatic). It may be selected from.

[0131] In some embodiments, the linker can be a non-linear chain, can be an aliphatic or aromatic or heteroaromatic cyclic moiety, or can include the cyclic moiety.

[0132] In some embodiments, the linker can include a group of ethylene glycol units that are continuous, partially continuous, or discontinuous, such as 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 5 ethylene glycol units, about 2 to about 4 ethylene glycol units in range, for example 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units.

[0133] In some embodiments, the linker can have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 fluorine substituents. In another embodiment, the linker can be perfluorinated. In a further embodiment, the linker can be a partially or fully fluorinated polyether. Non-limiting examples of fluorinated linkers include TIFF2025517099000082.tif168142.

[0134] Delivery of the compounds of the present disclosure (e.g., TCIP) into cells The present disclosure provides for delivering, into cells, a compound of the present disclosure (e.g., TCIP or CIP) in a manner sufficient to induce proximity of a first endogenous protein and a second endogenous protein as described above, for example as described above. Any convenient protocol for delivering the CIP compound into the cells can be used. The specific protocol used can vary, for example, depending on whether the target cells are in vitro or in vivo. In some specific cases, the CIP compound is delivered into the cells by contacting the cells with the CIP compound. In an in vitro protocol, the contacting of the CIP compound with the target cells can be performed using any convenient protocol. For example, the target cells can be maintained in a suitable culture medium and the CIP compound can be introduced into the culture medium as specifically shown in the figures.

[0135] In an in vivo protocol, any convenient dosing protocol may be used. Depending on the binding affinity of the CIP compound, the desired response, the mode of administration, the half-life, and the number of cells present, various protocols may be used. Thus, CIP can be incorporated into various formulations for therapeutic administration, for example, into a pharmaceutically acceptable vehicle (also referred to herein as a pharmaceutical delivery medium or carrier). More specifically, the CIP of the present disclosure can be formulated into a pharmaceutical composition for intravenous administration over a period of several days or weeks. This can be done by combining it with a suitable pharmaceutically acceptable carrier or diluent, and can be formulated into preparations in solid, semi-solid, liquid or gaseous form, such as tablets, capsules, powders, granules, ointments (e.g., skin creams), solutions, suppositories, injections, inhalants and aerosols. Therefore, administration of the agent (e.g., the compound of the present disclosure) can be carried out in various modes, such as oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intratracheal, intravenous, intravesical, subcutaneous, intramuscular, etc. In pharmaceutical dosage forms, CIP can be administered alone, or in appropriate association with other pharmaceutically active compounds, and in combination with other pharmaceutically active compounds. The following examples are illustrative and not limiting. In some cases, the compounds of the present disclosure can be formulated and / or administered in such a manner that they can cross the blood-brain barrier.

[0136] In oral preparations, the agent (e.g., the compound of the present disclosure) can be used alone or in combination with suitable additives for making tablets, powders, granules or capsules, for example, with conventional additives such as lactose, mannitol, corn starch or potato starch; binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatin; disintegrants such as corn starch, potato starch or sodium carboxymethyl cellulose; lubricants such as talc or magnesium stearate; and, if desired, in combination with diluents, buffers, humectants, preservatives and flavoring additives.

[0137] The agent (e.g., the compound of the present disclosure) can be dissolved, suspended, or emulsified in an aqueous or non-aqueous solvent, such as vegetable oil or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids, or propylene glycol; and, if desired, formulated into an injectable preparation together with conventional additives, such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers, and preservatives.

[0138] The agent (e.g., the compound of the present disclosure) may be used in an aerosol formulation for administration by inhalation. The compounds of the present disclosure can be formulated with a pressurized acceptable propellant, such as dichlorodifluoromethane, propane, nitrogen, etc.

[0139] Furthermore, the agent (e.g., the compound of the present disclosure) may be made into suppositories by mixing with various bases, such as emulsifying bases or water-soluble bases. The compounds of the present disclosure can be administered rectally by suppositories. The suppositories may contain a vehicle that melts at body temperature but solidifies at room temperature, such as cocoa butter, carbowax, and polyethylene glycol.

[0140] Unit dosage forms for oral or rectal administration, such as syrups, elixirs, and suspensions, may be provided, which contain a predetermined amount of a composition containing one or more inhibitors in each dosage unit, such as a teaspoonful, a tablespoonful, a tablet, or a suppository. Similarly, unit dosage forms for injection or intravenous administration may contain the inhibitor(s) in the composition as a solution in sterile water, physiological saline, or another pharmaceutically acceptable carrier.

[0141] As used herein, the term "unit dosage form" refers to a physically discrete unit suitable as a unit dosage for human and animal subjects, each unit containing a predetermined quantity of a compound of the present disclosure calculated to be in an amount sufficient to produce the desired effect, together with a pharmaceutically acceptable diluent, carrier or vehicle. Specific details of the novel unit dosage forms of the present disclosure will depend on the specific compound used, the effect to be achieved and the pharmacodynamics associated with each compound in the host.

[0142] Pharmaceutically acceptable excipients such as vehicles, adjuvants, carriers or diluents are readily available publicly. Further, pharmaceutically acceptable auxiliary substances such as pH adjusters and buffers, tonicity adjusting agents, stabilizers, wetting agents and the like are readily available publicly.

[0143] Those skilled in the art will readily recognize that dosage levels can vary as a function of the specific compound, the nature of the delivery medium, etc. The preferred dosage for a given compound is readily determined by those skilled in the art by a variety of means.

[0144] In embodiments where an effective amount of an active agent (e.g., a compound of the present disclosure) is administered to a living subject, the amount or dosage is effective for a suitable period, e.g., for a period of 1 week or more, e.g., 2 weeks or more, e.g., 3 weeks or more, 4 weeks or more, 8 weeks or more, etc., which demonstrates the desired therapeutic effect. For example, an effective dosage is one that, when administered, results in the desired therapeutic effect for a suitable period, e.g., at least about 1 week, optionally about 2 weeks, or longer, about 3 weeks, 4 weeks, 8 weeks, or longer. In some cases, the effective amount or dosage of the active agent (e.g., a compound of the present disclosure) not only retards or halts the progression of the disease state, but also induces reversal of the state, i.e., causes improvement of one or more symptoms of the state. For example, in some cases, an effective amount, when administered, is one that results in improvement of one or more symptoms of a subject suffering from a disease state for a suitable period, usually at least about 1 week, optionally about 2 weeks, or longer, about 3 weeks, 4 weeks, 8 weeks, or longer, where the magnitude of improvement (e.g., as measured using an appropriate protocol with a relevant control) can vary, e.g., 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, in some cases 6-fold, 7-fold, 8-fold, 9-fold or 10-fold or more.

[0145] In some specific embodiments, the method includes, at some point after supplying the CIP, removing the CIP from the cells. Removal of the CIP from the cells can be performed using any convenient protocol, e.g., by removing the CIP from the medium in which the cells are present, by stopping administration of the CIP to the animal containing the cells, by contacting the cells with an inhibitor of CIP-induced proximity, by contacting the cells with a molecule that binds to only one of a first endogenous protein or a second endogenous protein in exchange for the CIP, etc. An example of a specific type of inhibitor of the action of CIP would be a molecule consisting of only one side of a ligand of either the first endogenous protein or the second endogenous protein, without a linker or other moiety.

[0146] As summarized above, the present disclosure further provides a method for inductively modulating the transcription of a target gene. In a non-limiting example, the target gene is a pro-apoptotic gene. As described above, a pro-apoptotic gene is a gene whose expression product can promote or cause apoptosis, i.e., programmed cell death, in a multicellular organism, which can be characterized by various cell changes such as blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, fragmentation of chromosomal DNA, and overall mRNA degradation and death. Specific pro-apoptotic genes of interest related to transcription that can be enhanced in aspects of the present disclosure include, but are not limited to, PUMA (BBC3), BIM (BCL2L11), BID, BAX, BAK, BOK, BAD, HRK, BIK, BMF, and NOXA. In such cases, the magnitude of enhancement can vary, here including, for example, from substantially none to a certain degree of expression, and in some cases, the magnitude can be 2-fold or more, such as 5-fold or more, for example 10-fold or more. In another non-limiting example, the target gene is a survival factor (e.g., BCL-2, BCLX, and other factors that promote cell proliferation), and the expression of the survival factor can be reduced using the compositions, systems, and methods provided herein.

[0147] In some cases, the cell is a malignant cell, e.g., a cell of a subject suffering from a malignant condition (e.g., cancer), i.e., a cell taken from such a subject or a cell that is part of such a subject. For example, the cell can have high levels of BCL6 (or another BTB domain-containing protein) and other factors at normal or above-normal levels, such as ER, BRD4, target CDKs (e.g., CDK9, CDK8, and / or CDK7), AR, etc.), e.g., malignant / cancer cells, e.g., but not limited to, lung cancer cells (e.g., SCLC) or lymphoma cells, (e.g., DCBCL) cells, prostate cancer cells, leukemia cells, breast cancer cells, etc.

[0148] As summarized above, the present disclosure further provides a method for inducibly modulating the transcription of a target gene. Such a method comprises supplying a proximity chemical inducer (CIP) into a cell (e.g., a eukaryotic cell) containing a first endogenous protein and a second endogenous protein, such as those described above, under conditions sufficient to modulate the transcription of the target gene. The CIP and the cell can be as described above. The modulation of transcription can be various. In some cases, the modulation enhances the transcription of the gene, for example, by enhancing the desired activity in the cell when the gene is beneficial for a disease state, for example, enhancing the transcription of an apoptosis-promoting gene when cell death is desired, enhancing the expression of a therapeutically beneficial gene when an increase in the amount of the product of such a gene is beneficial for a given disease state, etc. In such cases, the magnitude of the enhancement can be various, where, by way of example, it includes from substantially none to a certain degree of expression, and in some cases, the magnitude can be 2-fold or more, for example, 5-fold or more, for example, 10-fold or more. In some cases, the modulation includes reducing the transcription of the target gene, for example, when the gene is harmful, such as the c-myc or triplet expansion gene, such as Huntington, etc. In such cases, the magnitude of the reduction can be various, where, by way of example, it includes from a certain degree of expression to substantially none even if there was expression, and in some cases, the magnitude of the reduction can be 2-fold or more, such as 5-fold or more, for example, 10-fold or more.

[0149] In some cases, the cell is a cell of a subject suffering from, diagnosed with, having, or suspected of having a disease state, i.e., a cell taken from such a subject or a cell that is part of such a subject. The disease states that the subject may be suffering from, diagnosed with, having, or suspected of having can be diverse, and examples of such disease states include, but are not limited to, neoplastic disease states such as cancer; nervous system pathologies, neurodevelopmental disorders, immune disorders, gastrointestinal diseases, cardiovascular diseases, and the like.

[0150] The compositions, systems, and methods of the present disclosure are believed to be useful in the treatment of a variety of different pathologies where modulation of the transcription of a target gene in a host is desired. Treatment is intended to achieve at least a remission of one or more of the symptoms associated with the pathology from which the host is suffering, where remission is used in a broad sense to indicate at least a reduction in a parameter associated with the pathology being treated, such as the magnitude of a symptom. Thus, treatment also includes situations where the pathological condition or at least the symptoms associated therewith are completely arrested, e.g., prevented from occurring, or stopped, e.g., terminated, such that the host no longer suffers from the pathological condition or at least the symptoms characterizing the pathological condition.

[0151] If the method is a method of treating a subject for a pathology, the method can further include, for example, assessing that the subject has the pathology in order to confirm that a given CIP is suitable for use in the treatment of the subject for a given pathology. Any convenient diagnostic protocol appropriate for the given pathology can be used, where the selection of such a protocol necessarily depends on the specific pathology being treated.

[0152] Non-limiting examples of conditions or diseases of a subject (e.g., a patient) that can be treated or ameliorated by the compositions, systems, and methods of the present disclosure include multiple sclerosis, various malignancies, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive abnormalities, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, (PKD1) or 4 (PKD2) Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, and Turner syndrome.

[0153] Further non-limiting examples of such conditions or diseases include those caused by microbial agents or other foreign agents, e.g., by viruses, bacteria, fungi, protozoa, or other microorganisms.

[0154] In some cases, the condition or disease of interest can be cancer. Non-limiting examples of cancer include adrenocortical cancer, AIDS-related cancers (e.g., Kaposi's sarcoma, lymphoma, etc.), anal cancer, appendiceal cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell cancer, bile duct cancer (extrahepatic and intrahepatic), bladder cancer, bone cancer (e.g., Ewing's sarcoma, osteosarcoma, and malignant fibrous histiocytoma, etc.), brainstem glioma, brain tumor (e.g., astrocytoma, central nervous system germinoma, central nervous system embryonal cell tumor, craniopharyngioma, ependymoma, etc.), breast cancer (e.g., female breast cancer, male breast cancer, pediatric breast cancer, etc.), bronchial tumor, carcinoid tumor (e.g., pediatric, gastrointestinal, etc.), cancer of unknown primary origin, heart (cardiac) tumor, central nervous system (e.g., atypical teratoid / rhabdoid tumor, germinoma, embryonal cell tumor, lymphoma, etc.), cervical cancer, pediatric cancer, chordoma, colon cancer, colorectal cancer, craniopharyngioma, ductal carcinoma in situ (DCIS), germinoma, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial embryonal cell tumor, extragonadal embryonal cell tumor, extrahepatic bile duct cancer, eye cancer (e.g., intraocular melanoma, retinoblastoma, etc.), fibrous histiocytoma of bone (e.g., malignant, osteosarcoma, etc.), gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), embryonal cell tumor (e.g., extracranial, extragonadal, ovarian, testicular, etc.), gestational trophoblastic disease, glioma, head and neck cancer, heart cancer, hepatocellular (liver) cancer, histiocytosis (e.g., Langerhans cell, etc.), hypopharyngeal cancer, intraocular melanoma, islet cell tumor (e.g., pancreatic neuroendocrine tumor, etc.), Kaposi's sarcoma, kidney cancer (e.g., renal cell, Wilms tumor, pediatric kidney tumor, etc.), Langerhans cell histiocytosis, laryngeal cancer, leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), aleukemic leukemia, acute non-lymphocytic leukemia, acute monocytic leukemia, acute granulocytic leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic granulocytic leukemia, adult T-cell leukemia, basophilic leukemia, eosinophilic leukemia, histiocytic leukemia, mast cell leukemia, megakaryocytic leukemia, blast cell leukemia, cutaneous leukemia, hairy cell leukemia, stem cell leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia,Lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, cancers of the lips and oral cavity, liver cancer (primary), lobular carcinoma in situ (LCIS), lung cancer (e.g., non-small cell, small cell, etc.), lymphoma (non-Hodgkin lymphoma or Hodgkin lymphoma: e.g., small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B cell) lymphoma, T cell lymphoma, splenic lymphoma, diffuse large B cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma or precursor B-lymphoblastic lymphoma, cutaneous T cell lymphoma, peripheral T cell lymphoma, undifferentiated large cell lymphoma, mycosis fungoides, primary central nervous system (CNS) lymphoma and precursor T-lymphoblastic lymphoma), macroglobulinemia (e.g., Waldenström, etc.), male breast cancer, malignant fibrous histiocytoma and osteosarcoma of bone, melanoma, Merkel cell cancer, mesothelioma, metastatic squamous cell carcinoma of the neck of unknown primary, midline tract cancer associated with the NUT gene, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasms, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, cancers of the nasal cavity and paranasal sinuses, nasopharyngeal cancer, neuroblastoma, non-small cell lung cancer, oral cancer, cancers of the oral cavity (e.g., lips, etc.), oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer (e.g., epithelial, germ cell tumor, low-grade potential tumor, etc.), pancreatic cancer, pancreatic neuroendocrine tumor (islet cell tumor), papillomatosis, paraganglioma, cancers of the paranasal sinuses and nasal cavity, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, renal pelvis and ureter, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (e.g., Ewing, Kaposi, osteosarcoma, rhabdomyosarcoma, soft tissue, uterine, etc.), Sézary syndrome, skin cancer (e.g., pediatric, melanoma, Merkel cell cancer, non-melanoma, etc.), small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous cell carcinoma of the neck (e.g., of unknown primary, metastatic, etc.), stomach (gastric) cancerTesticular cancer, throat cancer, thymoma and thymic cancer, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, cancer of the ureter and renal pelvis, urethral cancer, uterine cancer (e.g., endometrium, etc.), uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, Wilms tumor, etc. may be mentioned. Cancers that can be treated include epithelial cancers, such as cancer, such as lobular cell cancer, alveolar cell cancer, lobular vesicles, glandular cyst cancer, adenoid cystic cancer, adenoid squamous cancer, accessory organ cancer, adrenal cortical cancer, alveolar epithelial cancer, enamel epithelial cancer, apocrine cancer, basal cell cancer, bronchioloalveolar epithelial cancer, bronchiogenic cancer, cholangiocarcinoma, villous cancer, clear cell cancer, colloid cancer, cribriform cancer, non-invasive ductal breast cancer, fetal cancer, metastatic skin cancer, endometroid cancer, epidermoid cancer, cancer derived from mixed tumors, cancer derived from pleomorphic adenomas, follicular cancer of the thyroid, hepatocellular cancer, intraepithelial cancer, intraductal cancer, Hurthle cell cancer, inflammatory breast cancer, large cell cancer, invasive lobular cancer, lobular cancer, non-invasive lobular cancer (LCIS), medullary cancer, meningioma, Merkel cell cancer, mucinous cancer, mucinous epidermoid cancer, nasopharyngeal cancer, non-small cell cancer, non-small cell lung cancer (NSCLC), oat cell cancer, papillary cancer, renal cell cancer, squamous cancer, sebaceous gland cancer, simple cancer, signet ring cell cancer, small cell cancer, small cell lung cancer, spindle cell cancer, squamous epithelial cancer, terminal duct breast cancer, transitional epithelial cancer, tubular cancer, verrucous cancer, etc. may be further mentioned.

[0155] Various subjects can be treated by the methods of the subject. In some cases, the subject is a "mammal" or "mammalian", where these terms are used broadly to refer to organisms included within the class Mammalia, such as the order Carnivora (e.g., dogs and cats), the order Rodentia (e.g., mice, guinea pigs and rats), and the order Primates (e.g., humans, chimpanzees and monkeys). In some cases, the subject is a human.

[0156] Proximity Chemical Inducers and Treatment of Malignant Tumors In various aspects, the compositions, systems and methods provided herein are particularly useful for the treatment of malignant tumors (e.g., cancer). In some aspects of the present disclosure, the compositions, systems and methods are used to treat malignant tumors (e.g., cancer).

[0157] A malignant tumor is a term for a disease in which abnormal cells divide uncontrollably and can invade nearby tissues. Malignant cells can also spread to other parts of the body via the blood and lymphatic systems. There are several major types of malignant tumors. Cancer is a malignant tumor that occurs in the skin, or in tissues that line or cover internal organs. Sarcoma is a malignant tumor that occurs in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissues. Leukemia is a malignant tumor that occurs in hematopoietic tissues, such as the bone marrow, and is caused by the production of too many abnormal blood cells. Lymphoma and multiple myeloma are malignant tumors that occur in cells of the immune system. Cancers of the central nervous system are malignant tumors that occur in the tissues of the brain and spinal cord.

[0158] Lung cancer is the leading cause of cancer death worldwide, with 2.2 million new cases and 1.8 million deaths in 2020 alone (Sung et al., CA Cancer J. Clin. (2021) 71:209-249). Although survival rates have improved in most subtypes of lung cancer due to pharmacological and surgical advances, small cell lung cancer (SCLC) remains the most lethal, with a median survival time after diagnosis of less than 2 years if diagnosed early and approximately 1 year in patients with metastatic disease (Rudin et al., Nat. Rev. Dis. Primers (2021) 7:3). Therefore, there is an urgent need for new therapeutic agents for SCLC patients.

[0159] Small cell lung cancer (SCLC) is a highly malignant neuroendocrine cancer that accounts for 15% of all lung cancer cases. The estimated number of new cases per year is 250,000, and the number of deaths worldwide is 200,000. Approximately 98% of SCLC patients have some smoking history and are also associated with environmental toxin exposure (Varghese et al., J. Thorac. Oncol. (2014) 9:892-896). Up to 70% of patients are in TNM stage IV at diagnosis, and the survival rate at 24 months is 8% (Nicholson et al., J. Thorac. Oncol. (2016) 11:300-311). At initial diagnosis, the tumor often presents centrally with lymph node and / or metastatic invasion, and surgical options are limited (Rudin, supra). Evaluation of the genomic characteristics of SCLC has confirmed the co-inactivation of the tumor suppressors TP53 and RB in a significant proportion of SCLC cases (George et al., Nature (2015) 524:47-53). Furthermore, in SCLC, dysregulation of other cellular mechanisms involved in cell cycle arrest and apoptosis, such as MYC amplification and BCL-2 amplification, is occasionally seen (Little et al., Nature (1983) 306:194-196; Ikegaki et al., Cancer Res. (1994) 54:6-8). However, to date, there is no strong and druggable pathway or molecular target for therapeutic development.

[0160] Non-Hodgkin lymphoma (NHL) is a diverse group of blood cancers that includes any type of lymphoma other than Hodgkin lymphoma. The types of NHL vary considerably in their severity, from indolent to very aggressive. Low-aggressive non-Hodgkin lymphomas are compatible with long-term survival, while more aggressive non-Hodgkin lymphomas can be rapidly fatal if untreated. It can be formed from either B cells or T cells. B-cell non-Hodgkin lymphomas include Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma. T-cell non-Hodgkin lymphomas include mycosis fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblastic lymphoma. Prognosis and treatment depend on the stage and type of the disease.

[0161] Diffuse large B-cell lymphoma (DLBCL) DLBCL is the most common lymphoma and originates from germinal center B cells. Frontline treatment with the highly toxic aggressive regimen R-CHOP has favorable outcomes in approximately 60% of patients, but persistent neurological or cardiovascular disorders remain in some patients. DLBCL that is resistant to R-CHOP is difficult to treat and is an area with significant unmet needs. BCL6, MYC, BCL2, and STAT3 are well-established drivers of DLBCL and are targets of gene translocations and amplifications that are activated or overexpressed (Pasqualucci and Dalla-Favera, “Genetics of diffuse large B-cell lymphoma,” Blood (2018) 131:2307-2319; Schmitz, et al., “Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma,” N Engl J Med (2018) 378:1396-1407; and Reddy et al., “Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma,” Cell (2017) 171:481-494 e415). Such driver events occur in combination with each other in the case of double-hit / triple-hit lymphomas and in combination with numerous other genetic alterations that define five genetic subtypes of DLBCL (Schmitz et al., supra; Chapuy et al., “Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes,” Nat Med (2018) 24:679-690). There is clearly a need for new therapeutic agents that are less toxic and address the multiple driver issues in DLBCL.

[0162] Prostate cancer is the second most commonly diagnosed cancer in men and the sixth leading cause of cancer death, accounting for 14% (903,500 cases) of all newly occurring cancer cases and 6% (258,400 deaths) of all cancer deaths among men worldwide. The course of prostate cancer from diagnosis to death is best classified as a series of clinical stages based on the extent of the disease, hormonal status, and the presence or absence of detectable metastases: localized disease, rising prostate-specific antigen (PSA) levels without detectable metastases after radiation therapy or surgery, and clinical metastases in the non-orchiectomy or orchiectomy stage. Surgery, radiation, or a combination of both can be curative for patients with local disease, but a significant proportion of such patients have recurrent disease, particularly in the high-risk group of this disease, as indicated by rising PSA levels that can lead to the development of metastases during the transition to the lethal stage of this disease.

[0163] The incidence of cancer continues to increase with aging in the general population, with the occurrence of new cancers, and with the growth of susceptible populations. There is a vast and unmet need for new methods and compositions that can be used to treat cancer patients.

[0164] CIP for the treatment of malignancies The present disclosure provides methods for treating subjects for malignant tumors, such as lung cancer, cancers of the upper aerodigestive tract, hematopoietic malignancies, such as lymphoma, leukemia, sarcoma, GI cancers (e.g., cancers of the bile duct, pancreas, liver, colorectal, esophagus, stomach), breast cancer, prostate cancer, CNS malignancies (e.g., glioblastoma, astrocytoma), kidney cancer, urinary tract cancer, thyroid cancer, melanoma, ovarian cancer, soft tissue malignancies, uterine cancer, cervical cancer, and the like. As outlined above, in aspects of the methods, CIPs, such as transcriptional proximity chemical inducers (TCIPs), are used. A TCIP is a compound that induces proximity between a first endogenous anchor transcription factor, such as BCL-6 (and / or its functional homolog), that binds to the promoter of a target gene, such as a pro-apoptotic gene, and a second endogenous transcriptional modulation factor, such as a cancer cell driver, such as an SCLC or DLBCL driver, such as BRD4 or CDK (e.g., CDK9, CDK8, CDK7), a prostate cancer driver, such as an androgen receptor (AR), an estrogen receptor, etc., under intracellular conditions. Some CIPs of the present disclosure are capable of inducing proximity between at least one endogenous transcription factor or epigenetic regulator and another endogenous transcriptional modulation factor (e.g., BRD4, CDK, estrogen receptor, AR, etc.), and thus such CIPs of the present disclosure may be referred to as transcriptional proximity chemical inducers (TCIPs). The TCIPs of the present disclosure can be considered epigenetic proximity chemical inducers of transcription. By "inducing proximity," when used in reference to the compounds (CIP or TCIP) of the present disclosure, it is intended that a first endogenous protein and a second endogenous protein are spatially associated with each other by a binding event mediated by the compound configured to bind simultaneously to both endogenous proteins, and thus the compound can be considered a bifunctional compound or molecular glue. The spatial association is characterized by the presence of a ternary complex comprising the CIP, the first endogenous protein, and the second endogenous protein (e.g., BRD4, CDK, estrogen receptor, AR, etc.). In the ternary complex, each member or component of the ternary complex is bound to at least one other member of the ternary complex.In this ternary complex, the bonds between the various components can be diverse. For example, CIP can simultaneously bind to the first and second endogenous factors or protein domains, thereby generating a ternary complex and a desired spatial association, which, for example, ultimately results in the desired transcriptional modulation of the target gene. This ternary complex is composed of three different components bound by non-covalent bonds, such as a first endogenous protein, a second endogenous protein, and CIP. In the example of TCIP, the ternary complex is composed of three different components (e.g., an endogenous anchor transcription factor, an endogenous transcriptional modulation factor, and TCIP) bound by non-covalent bonds. Further details regarding CIP and TCIP can be found in the pending PCT application number PCT / US2021 / 058231, published as WO2022 / 098989, the disclosure of which is incorporated herein by reference.

[0165] In some aspects of the present disclosure, the TCIP compounds used are those that include a first ligand (and / or its functional homolog) that specifically binds to an anchor transcription factor, such as BCL-6, and a second ligand that specifically binds to a transcription modulation factor, such as BRD4, CDK, estrogen receptor, AR, etc., where the second ligand may be a second ligand linked by a second covalent bond. The first ligand and the second ligand can be stably associated with each other, for example, via a linker, which can be a bond or a linking group, and can result in a covalent bond linkage between the first ligand and the second ligand either directly or via a linking group as desired. In other words, in aspects where the TCIP compound includes a linker element, this can be a bond or a linking moiety that covalently links a first ligand that specifically binds to an anchor transcription factor and a second ligand that specifically binds to a transcription modulation factor. The terms "specific binding", "specifically binds", etc., when used in reference to TCIP, indicate the ability of the first and second ligands to preferentially bind directly to their corresponding anchor and transcription modulator factors compared to other molecules or moieties within the cell.

[0166] In some cases, the first and second ligands of TCIP are small molecules, which, in some cases, each have a molecular weight in the range of 50 Daltons to 1000 Daltons, for example, from 400 to 800 Daltons. The chemical structures of the first and second ligands can be widely diverse, where the first and second ligands can be selected such that the desired specific binding to the target anchor transcription factor or transcription modulation factor is obtained. The first and second ligands may be selected such that they have little, if any, effect on the activity of the endogenous factor of the object to which they are configured to bind, such as an anchor transcription factor or a transcription modulation factor.

[0167] As summarized above, the present disclosure provides compounds that are proximity chemical inducers. The following are specific examples of compounds that can be used in the compositions, systems, and methods provided herein. In a specific embodiment, the compounds of interest include a BCL-6 (B-cell lymphoma 6) inhibitor and a BRD4 (bromodomain-containing 4) ligand. In some embodiments, the BCL-6 inhibitor and the BRD4 ligand are covalently linked via a linker. In some embodiments, the proximity chemical inducer has the formula I: (BR or EL or CL or AL)-L-BC(I) Wherein: EL is a ligand that specifically binds to the estrogen receptor; BR is a ligand that specifically binds to bromodomain-containing protein 4 (BRD4); CL is a ligand that specifically binds to a CDK, such as CDK9, CDK8, and / or CDK7; AL is a ligand that specifically binds to the androgen receptor; BC is a ligand that specifically binds to B-cell lymphoma 6 (BCL-6) or a BCL6 BTB-domain family member; L is an optional linker or a pharmaceutically acceptable salt thereof is included.

[0168] In some embodiments, the "salt" of the compounds of the present disclosure includes: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucic acid, etc.; or (2) salts formed when the acidic protons present in the compound are replaced by metal ions such as alkali metal ions, alkaline earth metal ions or aluminum ions; or by ligands having an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.

[0169] As used herein, the term "solvate" refers to a complex or aggregate formed by one or more solute molecules, such as a compound of formula I (BR-L-BC) or a salt thereof, and one or more solvent molecules. Such solvates can be crystalline solids having a substantially fixed molar ratio of solute to solvent. Representative solvents include, by way of example, water, methanol, ethanol, isopropanol, acetic acid, etc. When the solvent is water, the solvate formed is a hydrate.

[0170] In some embodiments, the compounds described herein exist in isotopically labeled forms. For example, the compounds disclosed herein include the isotopically labeled compound that is identical to that described herein except that one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number typically found in nature. Examples of isotopes incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F, and 36Cl, respectively. The compounds described herein and their pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives containing the foregoing isotopes and / or other isotopes of other atoms are within the scope of the present invention. Some specific isotopically labeled compounds, such as those incorporated with radioactive isotopes, such as 3H and 14C, are useful in the tissue distribution assays of drugs and / or substrates. Tritiated forms, i.e., isotopes of 3H and carbon 14, i.e., 14C, are particularly preferred due to the ease of their preparation and detectability. Furthermore, substitution with heavy isotopes, such as deuterium, i.e., 2H, results in certain therapeutic advantages due to increased metabolic stability, such as an extended in vivo half-life or a reduced required dosage. In some embodiments, the isotopically labeled compound, its pharmaceutically acceptable salt, ester, solvate, hydrate, or derivative is prepared by any suitable method.

[0171] The compounds disclosed in this specification include their prodrugs. "Prodrug" as used herein is intended to mean a compound that can be converted to a biologically active compound described herein under physiological conditions or by solvolysis. The term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. A prodrug may be inactive when administered to a subject but is converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds can provide advantages such as solubility, tissue compatibility, and / or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 79, 2124 (Elsevier, Amsterdam)). Considerations of prodrugs are shown in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14 and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety. Prodrugs of the active compounds as described herein can be prepared by modifying the functional groups present in the active compounds in such a manner that the moiety is cleaved either by conventional manipulation or in vivo to yield the active parent compound.

[0172] BR: Bromodomain-containing 4 (BRD4) ligand Provided is a method of treating a subject for a malignant tumor, such as lung cancer (e.g., small cell lung cancer (SCLC)) or lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)). In some cases, the method may include administering a transcriptional proximity chemical inducer (TCIP) that links a BTB-domain-containing protein, such as BCL-6 or a related family member, and BRD4, to treat the subject for a malignant tumor, such as SCLC or DLBCL. Also provided are compositions that have been found to be useful in the practice of the methods of the present disclosure.

[0173] The TCIPs of the present disclosure used in such embodiments include ligands for transcriptional modulators, such as oncogenic transcription factors, such as BRD4. This embodiment is particularly important in the treatment of cancer, where the CIP causes the suicide of cancer cells by their own drivers. An oncogenic transcription factor is a transcription factor whose activity contributes to a neoplastic, e.g., cancerous, disease state. Oncogenic transcription factors can be various, and examples of oncogenic transcription factors that can be used in the treatment of SCLC include, but are not limited to, BRD4, c-myc, oncogenic fusion genes, and the like. Any convenient ligand for such oncogenic transcription factors can be used, and suitable ligands include the ability to enhance the transcription of a target apoptosis-promoting gene by the target oncogenic transcription factor when complexed with an anchor transcription factor, i.e., without any associated negative effect by the TCIP on the transcriptional activation activity of the target oncogenic transcription factor, and the ability to specifically bind to the target oncogenic transcription factor. The molecular weights of such ligands can vary, and in some cases, are in the range of 150 daltons to 500 daltons, such as 250 daltons to 400 daltons.

[0174] 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, and U.S. 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;Examples include those described in No. 20120157428; the disclosures of these are incorporated herein by reference.

[0175] 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, etc. The structures are shown below. TIFF2025517099000083.tif133146

[0176] In some embodiments, bromodomain-containing 4 ligand (BR) has the formula IA: TIFF2025517099000084.tif30128Wherein: 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- to 8-membered cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; B is a 3- to 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: R 3 and X together with the intervening atoms form a 5- to 6-membered cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl which may be substituted; Y is a covalent bond, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a divalent substituted C(1-6) hydrocarbon chain which may be replaced by one or more methylene units being -NR'-, -N(R')C(O)-, -C(O)N(R, -N(R')SO 2 -, -SO 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -; and is a divalent substituted C(1-6) hydrocarbon chain which may be replaced by -; Z is -CH 2 -, -NH, -O- or -S-; TIFF2025517099000085.tif2128 represents a single bond or a double bond; TIFF2025517099000086.tif2128 represents a bond with a linker; R 1 、R 2 、R 3 、R 4 and R 5 each independently is 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 and substituted sulfoximine ; and is such.

[0177] In some embodiments, A is a 5-membered fused heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some cases, A is a 5-membered fused heteroaryl ring having two heteroatoms independently selected from nitrogen or oxygen. In some cases, A is a 5-membered fused heteroaryl ring having two heteroatoms selected from nitrogen and oxygen. In some cases, A is a 5-membered fused heteroaryl ring having two heteroatoms independently selected from nitrogen or sulfur. In some cases, A is a 5-membered fused heteroaryl ring having two heteroatoms selected from nitrogen and sulfur. In some specific cases, A is selected from thiazolo ring, isothiazolo ring, oxazolo ring, isoxazolo ring, pyrazolo ring, and imidazolo ring. In some specific cases, A is isothiazolo.

[0178] In some embodiments, A is benzo, or a 5- to 6-membered fused heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some cases, A is a 5-membered fused heteroaryl ring having 2 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or a 6-membered fused heteroaryl ring having 2 to 3 nitrogen atoms. In some cases, A is benzo. In some embodiments, A is a 5- to 6-membered fused heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some cases, A is a 6-membered fused heteroaryl ring having 1 to 3 nitrogen atoms. In some specific cases, A is selected from pyrido ring, pyrimidine ring, pyrazino ring, pyridazine ring, and triazine ring. In some specific cases, A is a 5-membered fused heteroaryl ring having one heteroatom selected from nitrogen, oxygen, or sulfur. In some specific cases, A is thieno. In some specific cases, A is furano. In some specific cases, A is pyrrolo.

[0179] In some embodiments, B is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8- to 10-membered bicyclic saturated, partially unsaturated or aryl ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some cases, B is phenyl. In some cases, B is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring. In some specific cases, B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In some specific cases, B is cyclopentenyl, cyclohexenyl or cycloheptenyl.

[0180] In some embodiments, B is a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some specific embodiments, ring B is a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some specific embodiments, ring B is tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrohdinyl, pyrrohdonyl, piperidinyl, pyrrolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl or morpholinyl.

[0181] In some embodiments, B is a 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In some cases, B is a 6-membered heteroaryl ring having 1 nitrogen atom. In some cases, B is a 6-membered heteroaryl ring having 2 nitrogen atoms. In some cases, B is a 6-membered heteroaryl ring having 3 nitrogen atoms.

[0182] In some embodiments, B is a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some cases, B is a 5-membered heteroaryl ring having 1 heteroatom independently selected from nitrogen, oxygen, or sulfur. In some cases, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some cases, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen and oxygen. In some cases, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen and sulfur. In some cases, B is a 5-membered heteroaryl ring having 1 to 3 nitrogen atoms. In some specific cases, B is selected from thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0183] In some embodiments, B is a 7- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 5,5-fused-, 5,6-fused- or 6,6-fused saturated, partially unsaturated or aromatic bicyclic ring. In some cases, B is a 5,5-fused, 5,6-fused or 6,6-fused bicyclic aromatic ring. In some cases, B is a naphthalenyl, indanyl or indenyl group.

[0184] In some embodiments, B is a 7- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 7- to 8-membered bicyclic saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 7- to 8-membered bicyclic partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 9- to 10-membered bicyclic saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 9- to 10-membered bicyclic partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or quinuclidinyl. In some cases, B is selected from indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl or tetrahydroquinolinyl.

[0185] In some embodiments, B is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 5,5-fused, 5,6-fused, or 6,6-fused saturated, partially unsaturated, or aromatic bicyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some cases, B is a 5,5-fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some specific cases, B is a 5,5-fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1 to 4 nitrogen atoms. In some specific cases, B is a 5,6-fused heteroaryl ring having 1 to 4 nitrogen atoms. In some specific cases, B is pyrrolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, imidazopyridinyl, indazolyl, purinyl, cinnolinyl, quinazolinyl, phthalazinyl, naphthridinyl, quinoxalinyl, thianaphtheneyl, or benzofuranyl. In some specific cases, B is selected from indolizinyl, purinyl, naphthyridinyl, or pteridinyl.

[0186] In some embodiments, R 3 and X, together with the intervening atoms, form a heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some specific cases, R 3 and X, together with the intervening atoms, form an optionally substituted triazolyl ring. In some cases, R 3 is optionally substituted C(1-6) aliphatic. In some embodiments, R 3 is substituted. In some embodiments, R 3 is unsubstituted. In some specific embodiments, R 3 is C(1-6) alkyl. In some specific embodiments, R 3 is C(1-4) alkyl. In some specific embodiments, R3 is methyl, ethyl, propyl or isopropyl.

[0187] In some embodiments, X is oxygen or sulfur, or R 3 and X, together with the intervening atoms therebetween, form an optionally substituted 5-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, X is oxygen. In some embodiments, X is sulfur. In some embodiments, R 3 and X, together with the intervening atoms therebetween, form an optionally substituted 5-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 3 and X, together with the intervening atoms therebetween, form a substituted 5-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 3 and X, together with the intervening atoms therebetween, form an unsubstituted 5-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some specific embodiments, R 3 and X, together with the intervening atoms therebetween, form an optionally substituted 5-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some specific embodiments, R 3 and X, together with the intervening atoms therebetween, form an optionally substituted pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl or oxadiazolyl ring.

[0188] In some embodiments, R 4 is -R, halogen, -OR, -SR, -N(R') 2 , -CN, -NO 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R')2 、 -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 、 -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 、 -N(R')C(O)R, -N(R')C(O)N(R') 2 、 -N(R')C(S)N(R') 2 、 -N(R')SO 2 R, -N(R')SO 2 N(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 wherein R and R' are as defined and described herein. In some embodiments, R 4 is -R. In some specific embodiments, R 4 is hydrogen. In some other specific embodiments, R 4 is halogen. In some embodiments, R 4 is -OR, -SR or -N(R') 2 - In some specific cases where it is, R 4 is -OR. In some specific cases, R 4 is -CN or -NO 2 - In some specific cases, R 4 is -C(O)R, -CO 2 R, -C(O)N(R') 2 、 -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 or -C(S)OR. In some specific cases, R 4 is -S(O)R, -SO 2 R or -SO 2 N(R') 2 - In some specific cases, R 4is -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(R') 2 , -N(R')N(R') 2 or -N(R')C(=N(R'))N(R') 2 is. In some specific cases, R 4 is -C=NN(R') 2 , -C=NOR, -C(=N(R'))N(R') 2 is. In some specific cases, R 4 is -OC(O)R or -OC(O)N(R') 2 .

[0189] In some embodiments, m is an integer from 0 to 5. In some cases, m is 1. In some cases, m is 2. In some cases, m is 3. In some cases, m is 4. In some specific cases, m is 5.

[0190] In some embodiments, R 5 is -R, halogen, -OR, -SR, -N(R') 2 , -CN, -NO 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(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 wherein R and R' are as defined and described herein. In some embodiments, R 5 is -R. In some specific embodiments, R 5 is hydrogen. In some other specific embodiments, R 5 is halogen. In some embodiments, R 4 is -OR, -SR or -N(R') 2 -. In some specific embodiments, R 5 is -OR. In other embodiments, R 5 is -CN or -NO 2 . In some embodiments, R 5 is -C(O)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 or -C(S)OR. In other embodiments, R 5 is -S(O)R, -SO 2 R or -SO 2 N(R') 2 . In some specific embodiments, R 5 is -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(R') 2 , -N(R')N(R') 2 or -N(R')C(=N(R'))N(R') 2 . In some other specific embodiments, R 5 is -C=NN(R') 2 , -C=NOR, -C(=N(R'))N(R') 2 . In still other embodiments, R 5 is -OC(O)R or -OC(O)N(R') 2 .

[0191] In some embodiments, p is an integer from 0 to 5. In some cases, p is 1. In some cases, p is 2. In some cases, p is 3. In some cases, p is 4. In some cases, p is 5.

[0192] In some embodiments, Y is a covalent bond. In some cases, Y is a divalent C(1-6) hydrocarbon chain which may be substituted or unsubstituted and in which one or two methylene units may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -. In some cases, Y is a divalent C(1-3) hydrocarbon chain which may be substituted or unsubstituted and in which one methylene unit may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R, -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -. In some specific embodiments, Y is a C 2 ~3 hydrocarbon chain which may be replaced by -NH-, -O-, -S-, -S(O)- or -SO 1 -.

[0193] In some embodiments, each R 1 is independently hydrogen, halogen, optionally substituted C(1-6) aliphatic, -OR, -SR, -CN, -N(R') 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2, -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')S0 2 N(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 -(CH 2 ) q R x Selected from, where q is 0 to 3 and R x Is halogen, optionally substituted C(1-6) aliphatic, -OR, -SR, -CN, -N(R') 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(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 Is. In some embodiments, each R 1 Is independently selected from hydrogen and C(1-6) alkyl. In some cases, each R 1is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, each R 1 is independently C(1-6) aliphatic, -OR, -N(R') 2 , -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR' or -CO 2 R.

[0194] In some embodiments, each R 2 is independently hydrogen, halogen, optionally substituted C(1-6) aliphatic, -OR, -SR, -CN, -N(R') 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')S0 2 N(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 -(CH 2 ) q R x where q is 0-3 and R x is halogen, optionally substituted C(1-6) aliphatic, -OR, -SR, -CN, -N(R') 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2, -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(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 is. In some embodiments, each R 2 is independently selected from hydrogen and C(1-6) alkyl. In some cases, each R 2 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, each R 2 is independently C(1-6) aliphatic, -OR, -N(R') 2 , -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR' or -CO 2 R.

[0195] In some embodiments, n is an integer from 0 to 12. In some cases, n is 1. In some cases, n is 2. In some cases, n is 3. In some cases, n is 4. In some cases, n is 5. In some cases, n is 6.

[0196] In some embodiments, Z is -CH 2 . In some cases, Z is -NH. In some cases, Z is -O-. In some cases, Z is -S-.

[0197] In some embodiments, bromodomain-containing 4 ligand (BR) has the formula IA1: TIFF2025517099000087.tif32128Wherein: X 1 is C, N, O or S; X 2 is C, N, O or S; X 3 is C or N; TIFF2025517099000088.tif2128represents a single bond or a double bond; R 6 is 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 is of.

[0198] In some cases, X1 is N or O; X2 is N; X3 is C or N. In some cases, X 1 is N; X 2 is N; X 3 is N. In some cases, X 1 is O; X 2 is N; X 3 is C.

[0199] In some cases, R 6 is hydrogen or C(1-6)alkyl. In some cases, R 6 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 6 is methyl.

[0200] In some embodiments, n is an integer from 0 to 4. In some cases, n is 1. In some cases, n is 2. In some cases, n is 3. In some cases, n is 4. In some cases, n is 5. In some cases, n is 6.

[0201] In some embodiments, each R 1 is independently selected from hydrogen and C(1-6) alkyl. In some cases, each R 1 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, each R 1 is independently selected from C(1-6) aliphatic, -OR, -N(R') 2 , -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR' or -CO 2 R. In some cases, each R 1 is hydrogen or C(1-6) alkyl. In some cases, each R 1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, each R 1 is methyl.

[0202] In some embodiments, each R 2 is independently selected from hydrogen and C(1-6) alkyl. In some cases, each R 2 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, each R 2 is independently selected from C(1-6) aliphatic, -OR, -N(R') 2 , -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR' or -CO 2 R. In some cases, each R 2 is hydrogen or C(1-6) alkyl. In some cases, each R 2is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, each R 2 is methyl.

[0203] In some specific embodiments, n is an integer from 1 to 4; R 1 and R 2 each is independently selected from hydrogen and C(1-6) alkyl. In some specific cases, n is an integer from 1 to 4, and R 1 and R 2 each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, n is an integer from 1 to 4, and R 1 and R 2 each is methyl. In some specific cases, n is 1, and R 1 and R 2 each is hydrogen. In some specific cases, n is 1, and R 1 and R 2 each is methyl.

[0204] In some embodiments, A is a 5-membered fused heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some cases, A is a 5-membered fused heteroaryl ring having 2 heteroatoms independently selected from nitrogen or oxygen. In some cases, A is a 5-membered fused heteroaryl ring having 2 heteroatoms selected from nitrogen and oxygen. In some cases, A is a 5-membered fused heteroaryl ring having 2 heteroatoms independently selected from nitrogen or sulfur. In some cases, A is a 5-membered fused heteroaryl ring having 2 heteroatoms selected from nitrogen and sulfur. In some specific cases, A is selected from thiazolo ring, isothiazolo ring, oxazolo ring, isoxazolo ring, pyrazolo ring and imidazolo ring. In some specific cases, A is isothiazolo.

[0205] In some embodiments, A is a 5- to 6-membered fused heteroaryl ring having 1 to 3 heteroatoms independently selected from benzos, or nitrogen, oxygen or sulfur. In some cases, A is a 5-membered fused heteroaryl ring having 2 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur or a 6-membered fused heteroaryl ring having 2 to 3 nitrogen atoms. In some cases, A is benzo. In some embodiments, A is a 5- to 6-membered fused heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some cases, A is a 6-membered fused heteroaryl ring having 1 to 3 nitrogen atoms. In some specific cases, A is selected from a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring and a triazine ring. In some specific cases, A is a 5-membered fused heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen or sulfur. In some specific cases, A is thieno. In some specific cases, A is furo. In some specific cases, A is pyrrolo.

[0206] In some embodiments, B is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8- to 10-membered bicyclic saturated, partially unsaturated or aryl ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some cases, B is phenyl. In some cases, B is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring. In some specific cases, B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In some specific cases, B is cyclopentenyl, cyclohexenyl or cycloheptenyl.

[0207] In some embodiments, B is a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some specific embodiments, ring B is a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some specific embodiments, ring B is tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, or morpholinyl.

[0208] In some embodiments, B is a 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In some cases, B is a 6-membered heteroaryl ring having 1 nitrogen atom. In some cases, B is a 6-membered heteroaryl ring having 2 nitrogen atoms. In some cases, B is a 6-membered heteroaryl ring having 3 nitrogen atoms.

[0209] In some embodiments, B is a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some cases, B is a 5-membered heteroaryl ring having 1 heteroatom independently selected from nitrogen, oxygen, or sulfur. In some cases, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some cases, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen and oxygen. In some cases, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen and sulfur. In some cases, B is a 5-membered heteroaryl ring having 1 to 3 nitrogen atoms. In some specific cases, B is selected from thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0210] In some embodiments, B is a 7- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 5,5-fused-, 5,6-fused- or 6,6-fused saturated, partially unsaturated or aromatic bicyclic ring. In some cases, B is a 5,5-fused, 5,6-fused or 6,6-fused bicyclic aromatic ring. In some cases, B is a naphthalenyl, indanyl or indenyl group.

[0211] In some embodiments, B is a 7- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 7- to 8-membered bicyclic saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 7- to 8-membered bicyclic partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 9- to 10-membered bicyclic saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 9- to 10-membered bicyclic partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, or quinuclidinyl. In some cases, B is selected from indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.

[0212] In some embodiments, B is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 5,5-fused, 5,6-fused, or 6,6-fused saturated, partially unsaturated, or aromatic bicyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some cases, B is a 5,5-fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some specific cases, B is a 5,5-fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1 to 4 nitrogen atoms. In some specific cases, B is a 5,6-fused heteroaryl ring having 1 to 4 nitrogen atoms. In some specific cases, B is pyrrolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, imidazopyridinyl, indazolyl, purinyl, cinnolinyl, quinazolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, thianaphthenyl, or benzofuranyl. In some specific cases, B is selected from indolizinyl, purinyl, naphthyridinyl, or pteridinyl.

[0213] In some embodiments, R 4 is -R, halogen, -OR, -SR, -N(R') 2 , -CN, -NO 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(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, R 4 is -R. In some specific embodiments, R 4 is hydrogen. In some other specific embodiments, R 4 is halogen. In some embodiments, R 4 is -OR, -SR or -N(R') 2 -. In some specific cases, R 4 is -OR. In some specific cases, R 4 is -CN or -NO 2 -. In some specific cases, R 4 is -C(O)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 or -C(S)OR. In some specific cases, R 4 is -S(O)R, -SO 2 R or -SO 2 N(R') 2 -. In some specific cases, R 4 is -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(R') 2 , -N(R')N(R') 2 or -N(R')C(=N(R'))N(R') 2 . In some specific cases, R 4 is -C=NN(R') 2 , -C=NOR, -C(=N(R'))N(R') 2 . In some specific cases, R 4is -OC(O)R or -OC(O)N(R') 2 is.

[0214] In some embodiments, m is an integer from 0 to 5. In some cases, m is 1. In some cases, m is 2. In some cases, m is 3. In some cases, m is 4. In some specific cases, m is 5.

[0215] In some embodiments, R 5 is -R, halogen, -OR, -SR, -N(R') 2 , -CN, -NO 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(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 wherein R and R' are as defined and described herein. In some embodiments, R 5 is -R. In some specific embodiments, R 5 is hydrogen. In some other specific embodiments, R 5 is halogen. In some embodiments, R 4 is -OR, -SR or -N(R') 2 -. In some specific embodiments, R5 is -OR. In other embodiments, R 5 is -CN or -NO 2 . In some embodiments, R 5 is -C(O)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 or -C(S)OR. In other embodiments, R 5 is -S(O)R, -SO 2 R or -SO 2 N(R') 2 . In some specific embodiments, R 5 is -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(R') 2 , -N(R')N(R') 2 or -N(R')C(=N(R'))N(R') 2 . In some other specific embodiments, R 5 is -C=NN(R') 2 , -C=NOR, -C(=N(R'))N(R') 2 . In still other embodiments, R 5 is -OC(O)R or -OC(O)N(R') 2 .

[0216] In some embodiments, p is an integer from 0 to 5. In some cases, p is 1. In some cases, p is 2. In some cases, p is 3. In some cases, p is 4. In some cases, p is 5.

[0217] In some embodiments, Y is a covalent bond. In some cases, Y is such that one or two methylene units are -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO 2 -, -SO 2-N(R'), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 a divalent C(1-6) hydrocarbon chain which may be replaced by - and which may be substituted. In some cases, Y is such that one methylene unit is -NR'-, -N(R')C(O)-, -C(O)N(R, -N(R')SO 2 -, -SO 2 -N(R'), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 a divalent C(1-3) hydrocarbon chain which may be replaced by - and which may be substituted. In some specific embodiments, Y is such that one methylene unit is -NH-, -O-, -S-, -S(O)- or -SO 2 a C 1 ~3 hydrocarbon chain which may be replaced by -

[0218] In some embodiments, each R 1 is independently hydrogen, halogen, optionally substituted C(1-6) aliphatic, -OR, -SR, -CN, -N(R') 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')S0 2 N(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 -(CH 2 ) q R x selected from, where q is 0 to 3, and R x is halogen, optionally substituted C(1-6) aliphatic, -OR, -SR, -CN, -N(R') 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(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 is. In some embodiments, each R 1 is independently selected from hydrogen and C(1-6) alkyl. In some cases, each R 1 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, each R 1 is independently selected from C(1-6) aliphatic, -OR, -N(R') 2 , -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR' or -CO 2 R.

[0219] In some embodiments, each R 2independently is hydrogen, halogen, optionally substituted C(1-6) aliphatic, -OR, -SR, -CN, -N(R') 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')S0 2 N(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 -(CH 2 ) q R x selected from, where q is 0-3, and R x is halogen, optionally substituted C(1-6) aliphatic, -OR, -SR, -CN, -N(R') 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(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 is. In some embodiments, each R 2 is independently selected from hydrogen and C(1-6) alkyl. In some cases, each R 2 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, each R 2 is independently C(1-6) aliphatic, -OR, -N(R') 2 , -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR' or -CO 2 R.

[0220] In some embodiments, n is an integer from 0 to 12. In some cases, n is 1. In some cases, n is 2. In some cases, n is 3. In some cases, n is 4. In some cases, n is 5. In some cases, n is 6.

[0221] In some embodiments, Z is -CH 2 . In some cases, Z is -NH. In some cases, Z is -O-. In some cases, Z is -S-.

[0222] In some embodiments, the bromodomain-containing 4 ligand (BR) is of formula IA2: TIFF2025517099000089.tif38128 wherein: X 1 is C, N, O or S; X 2 is C, N, O or S; X 3 is C or N; X 4 is CH2 is NH, O or S; TIFF2025517099000090.tif2128 represents a single bond or a double bond; R 6 , R 7 and R 8 each independently is 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 of which.

[0223] In some embodiments, X 4 is S. In some specific cases, TIFF2025517099000091.tif2128 represents a double bond. In some embodiments, X 1 is N or O; X 2 is N; X 3 is C or N. In some embodiments, X 1 is N; X 2 is N; X 3 is N.

[0224] In some cases, R 6 is hydrogen or C(1-6)alkyl. In some cases, R 6 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 6 is methyl. In some cases, R 7 is hydrogen or C(1-6)alkyl. In some cases, R 7 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R7 is methyl. In some cases, R 8 is hydrogen or C(1-6) alkyl. In some cases, R 8 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 8 is methyl. In some specific cases, R 6 , R 7 and R 8 each is methyl.

[0225] In some embodiments, B is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8- to 10-membered bicyclic saturated, partially unsaturated or aryl ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some cases, B is phenyl. In some cases, B is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring. In some specific cases, B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In some specific cases, B is cyclopentenyl, cyclohexenyl or cycloheptenyl.

[0226] In some embodiments, B is a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some specific embodiments, ring B is a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some specific embodiments, ring B is tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, or morpholinyl.

[0227] In some embodiments, B is a 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In some cases, B is a 6-membered heteroaryl ring having 1 nitrogen atom. In some cases, B is a 6-membered heteroaryl ring having 2 nitrogen atoms. In some cases, B is a 6-membered heteroaryl ring having 3 nitrogen atoms.

[0228] In some embodiments, B is a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some cases, B is a 5-membered heteroaryl ring having 1 heteroatom independently selected from nitrogen, oxygen, or sulfur. In some cases, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some cases, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen and oxygen. In some cases, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen and sulfur. In some cases, B is a 5-membered heteroaryl ring having 1 to 3 nitrogen atoms. In some specific cases, B is selected from thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0229] In some embodiments, B is a 7- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 5,5-fused-, 5,6-fused- or 6,6-fused saturated, partially unsaturated or aromatic bicyclic ring. In some cases, B is a 5,5-fused, 5,6-fused or 6,6-fused bicyclic aromatic ring. In some cases, B is a naphthalenyl, indanyl or indenyl group.

[0230] In some embodiments, B is a 7- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 7- to 8-membered bicyclic saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 7- to 8-membered bicyclic partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 9- to 10-membered bicyclic saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 9- to 10-membered bicyclic partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, or quinuclidinyl. In some cases, B is selected from indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.

[0231] In some embodiments, B is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 5,5-fused, 5,6-fused, or 6,6-fused saturated, partially unsaturated, or aromatic bicyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some cases, B is a 5,5-fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some specific cases, B is a 5,5-fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1 to 4 nitrogen atoms. In some specific cases, B is a 5,6-fused heteroaryl ring having 1 to 4 nitrogen atoms. In some specific cases, B is pyrrolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, imidazopyridinyl, indazolyl, purinyl, cinnolinyl, quinazolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, thianaphthenyl, or benzofuranyl. In some specific cases, B is selected from indolizinyl, purinyl, naphthyridinyl, or pteridinyl.

[0232] In some embodiments, R 5 is -R, halogen, -OR, -SR, -N(R') 2 , -CN, -NO 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(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 wherein R and R' are as defined and described herein. In some embodiments, R 5 is -R. In some particular embodiments, R 5 is hydrogen. In some other particular embodiments, R 5 is halogen. In some embodiments, R 4 is -OR, -SR or -N(R') 2 . In some particular embodiments, R 5 is -OR. In other embodiments, R 5 is -CN or -NO 2 . In some embodiments, R 5 is -C(O)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 or -C(S)OR. In other embodiments, R 5 is -S(O)R, -SO 2 R or -SO 2 N(R') 2 . In some particular embodiments, R 5 is -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(R') 2 , -N(R')N(R') 2 or -N(R')C(=N(R'))N(R') 2 . In some other particular embodiments, R 5 is -C=NN(R') 2 , -C=NOR, -C(=N(R'))N(R') 2 . In still other embodiments, R 5is -OC(O)R or -OC(O)N(R') 2 is.

[0233] In some embodiments, p is an integer from 0 to 5. In some cases, p is 1. In some cases, p is 2. In some cases, p is 3. In some cases, p is 4. In some cases, p is 5.

[0234] In some embodiments, Y is a covalent bond. In some cases, Y is a divalent C(1-6) hydrocarbon chain which may be substituted or unsubstituted, wherein one or two methylene units are replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -. In some cases, Y is a divalent C(1-3) hydrocarbon chain which may be substituted or unsubstituted, wherein one methylene unit is replaced by -NR'-, -N(R')C(O)-, -C(O)N(R, -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -. In some specific embodiments, Y is a C 2 ~3 hydrocarbon chain which may be replaced by -NH-, -O-, -S-, -S(O)- or -SO 1 -.

[0235] In some embodiments, each R 1 is independently hydrogen, halogen, optionally substituted C(1-6) aliphatic, -OR, -SR, -CN, -N(R') 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2, -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')S0 2 N(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 -(CH 2 ) q R x selected from, where q is 0 to 3, and R x is halogen, optionally substituted C(1 - 6) aliphatic, -OR, -SR, -CN, -N(R') 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(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 is. In some embodiments, each R 1is independently selected from hydrogen and C(1-6) alkyl. In some cases, each R 1 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, each R 1 is independently C(1-6) aliphatic, -OR, -N(R') 2 , -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR' or -CO 2 R.

[0236] In some embodiments, each R 2 is independently hydrogen, halogen, optionally substituted C(1-6) aliphatic, -OR, -SR, -CN, -N(R') 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')S0 2 N(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 -(CH 2 ) q R x , where q is 0-3 and R x is halogen, optionally substituted C(1-6) aliphatic, -OR, -SR, -CN, -N(R') 2, -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(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 is. In some embodiments, each R 2 is independently selected from hydrogen and C(1-6) alkyl. In some cases, each R 2 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, each R 2 is independently C(1-6) aliphatic, -OR, -N(R') 2 , -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR' or -CO 2 R.

[0237] In some embodiments, n is an integer from 0 to 12. In some cases, n is 1. In some cases, n is 2. In some cases, n is 3. In some cases, n is 4. In some cases, n is 5. In some cases, n is 6.

[0238] In some embodiments, Z is -CH 2It is so. In some cases, Z is -NH. In some cases, Z is -O-. In some cases, Z is -S-.

[0239] In some embodiments, the bromodomain-containing 4 ligand (BR) has the formula IA3: TIFF2025517099000092.tif47128Wherein: X 1 is C, N, O or S; X 2 is C, N, O or S; X 3 is C or N; TIFF2025517099000093.tif2128represents a single bond or a double bond; R 6 、R 7 、R 8 、R 9 and R 10 each independently is 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 is such.

[0240] In some cases, X 1 is N or O; X 2 is N; X 3 is C or N. In some cases, X 1 is N; X 2 is N; X 3 is N. In some cases, X 1 is O; X 2 is N; X 3 is C.

[0241] In some cases, R 6 is hydrogen or C(1-6) alkyl. In some cases, R 6 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 6 is methyl. In some cases, R 7 is hydrogen or C(1-6) alkyl. In some cases, R 7 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 7 is hydrogen. In some cases, R 8 is hydrogen or C(1-6) alkyl. In some cases, R 8 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 8 is hydrogen. In some cases, R 9 is hydrogen or C(1-6) alkyl. In some cases, R 9 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 9 is hydrogen. In some cases, R 10 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 10 is hydrogen. In some specific cases, R 6 is methyl, and R 7 , R 8 R 9 and R 10 are each hydrogen.

[0242] In some cases, TIFF2025517099000094.tif6128 represents a double bond; TIFF2025517099000095.tif6128 represents a single bond.

[0243] In some embodiments, B is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8- to 10-membered bicyclic saturated, partially unsaturated or aryl ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some cases, B is phenyl. In some cases, B is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring. In some specific cases, B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In some specific cases, B is cyclopentenyl, cyclohexenyl or cycloheptenyl.

[0244] In some embodiments, B is a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some specific embodiments, ring B is a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some specific embodiments, ring B is tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl or morpholinyl.

[0245] In some embodiments, B is a 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In some cases, B is a 6-membered heteroaryl ring having 1 nitrogen atom. In some cases, B is a 6-membered heteroaryl ring having 2 nitrogen atoms. In some cases, B is a 6-membered heteroaryl ring having 3 nitrogen atoms.

[0246] In some embodiments, B is a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some cases, B is a 5-membered heteroaryl ring having 1 heteroatom independently selected from nitrogen, oxygen, or sulfur. In some cases, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some cases, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen and oxygen. In some cases, B is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen and sulfur. In some cases, B is a 5-membered heteroaryl ring having 1 to 3 nitrogen atoms. In some specific cases, B is selected from thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0247] In some embodiments, B is a 7- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 5,5-fused-, 5,6-fused- or 6,6-fused saturated, partially unsaturated or aromatic bicyclic ring. In some cases, B is a 5,5-fused, 5,6-fused or 6,6-fused bicyclic aromatic ring. In some cases, B is a naphthalenyl, indanyl or indenyl group.

[0248] In some embodiments, B is a 7- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 7- to 8-membered bicyclic saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 7- to 8-membered bicyclic partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 9- to 10-membered bicyclic saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 9- to 10-membered bicyclic partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or quinuclidinyl. In some cases, B is selected from indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl or tetrahydroquinolinyl.

[0249] In some embodiments, B is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, B is a 5,5-fused, 5,6-fused, or 6,6-fused saturated, partially unsaturated, or aromatic bicyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some cases, B is a 5,5-fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some specific cases, B is a 5,5-fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1 to 4 nitrogen atoms. In some specific cases, B is a 5,6-fused heteroaryl ring having 1 to 4 nitrogen atoms. In some specific cases, B is pyrrolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, imidazopyridinyl, indazolyl, purinyl, cinnolinyl, quinazolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, thianaphthenyl, or benzofuranyl. In some specific cases, B is selected from indolizinyl, purinyl, naphthyridinyl, or pteridinyl.

[0250] In some embodiments, R 5 is -R, halogen, -OR, -SR, -N(R') 2 , -CN, -NO 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(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 wherein R and R' are as defined and described herein. In some embodiments, R 5 is -R. In some specific embodiments, R 5 is hydrogen. In some other specific embodiments, R 5 is halogen. In some embodiments, R 4 is -OR, -SR or -N(R') 2 . In some specific embodiments, R 5 is -OR. In other embodiments, R 5 is -CN or -NO 2 . In some embodiments, R 5 is -C(O)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 or -C(S)OR. In other embodiments, R 5 is -S(O)R, -SO 2 R or -SO 2 N(R') 2 . In some specific embodiments, R 5 is -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(R') 2 , -N(R')N(R') 2 or -N(R')C(=N(R'))N(R') 2 . In some other specific embodiments, R 5 is -C=NN(R') 2 , -C=NOR, -C(=N(R'))N(R') 2 . In still other embodiments, R 5is -OC(O)R or -OC(O)N(R') 2 is.

[0251] In some embodiments, p is an integer from 0 to 5. In some cases, p is 1. In some cases, p is 2. In some cases, p is 3. In some cases, p is 4. In some cases, p is 5.

[0252] In some embodiments, Y is a covalent bond. In some cases, Y is a divalent C(1-6) hydrocarbon chain which may be substituted or unsubstituted, where one or two methylene units are replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -. In some cases, Y is a divalent C(1-3) hydrocarbon chain which may be substituted or unsubstituted, where one methylene unit is replaced by -NR'-, -N(R')C(O)-, -C(O)N(R, -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -. In some specific embodiments, Y is a C 2 ~3 hydrocarbon chain which may be replaced by -NH-, -O-, -S-, -S(O)- or -SO 1 -.

[0253] In some embodiments, each R 1 is independently hydrogen, halogen, optionally substituted C(1-6) aliphatic, -OR, -SR, -CN, -N(R') 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2, -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')S0 2 N(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 -(CH 2 ) q R x selected from, where q is 0 to 3 and R x is halogen, optionally substituted C(1 - 6) aliphatic, -OR, -SR, -CN, -N(R') 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(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 is. In some embodiments, each R 1is independently selected from hydrogen and C(1-6) alkyl. In some cases, each R 1 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, each R 1 is independently C(1-6) aliphatic, -OR, -N(R') 2 , -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR' or -CO 2 R.

[0254] In some embodiments, each R 2 is independently hydrogen, halogen, optionally substituted C(1-6) aliphatic, -OR, -SR, -CN, -N(R') 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')S0 2 N(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 -(CH 2 ) q R x where q is 0-3 and R x is halogen, optionally substituted C(1-6) aliphatic, -OR, -SR, -CN, -N(R') 2, -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(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 is. In some embodiments, each R 2 is independently selected from hydrogen and C(1-6) alkyl. In some cases, each R 2 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, each R 2 is independently C(1-6) aliphatic, -OR, -N(R') 2 , -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR' or -CO 2 R.

[0255] In some embodiments, n is an integer from 0 to 12. In some cases, n is 1. In some cases, n is 2. In some cases, n is 3. In some cases, n is 4. In some cases, n is 5. In some cases, n is 6.

[0256] In some embodiments, Z is -CH 2It is so. In some cases, Z is -NH. In some cases, Z is -O-. In some cases, Z is -S-.

[0257] In some embodiments, the bromodomain-containing 4 ligand (BR) has the formula IA4: TIFF2025517099000096.tif39128Wherein: n is an integer from 0 to 12; m is an integer from 0 to 5; X 1 is C, N, O or S; X 2 is C, N, O or S; X 3 is C or N; TIFF2025517099000097.tif2128 represents a single bond or a double bond; TIFF2025517099000098.tif2128 represents a bond to a linker; R 1 , R 2 , R 4 , R 6 , R 11 , R 12 , R 13 , R 14 and R 15 each independently is 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 of which.

[0258] In some cases, X 1 is N or O; X 2 is N; X 3 is C or N. In some cases, X1 is N; X 2 is N; X 3 is N. In some cases, X 1 is O; X 2 is N; X 3 is C.

[0259] In some cases, R 6 is hydrogen or C(1-6) alkyl. In some cases, R 6 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 6 is methyl.

[0260] In some cases, R 11 is selected from hydrogen, halogen or C(1-6) alkyl. In some cases, R 11 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 11 is hydrogen. In some cases, R 12 is selected from hydrogen, halogen or C(1-6) alkyl. In some cases, R 12 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 12 is hydrogen. In some cases, R 13 is selected from hydrogen, halogen or C(1-6) alkyl. In some cases, R 13 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 13 is hydrogen. In some specific cases, R 13 is halogen. In some specific cases, R 13 is selected from fluorine, chlorine, bromine and iodine. In some specific cases, R 13 is chlorine. In some cases, R 14is selected from hydrogen, halogen or C(1-6) alkyl. In some cases, R 14 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 14 is hydrogen. In some cases, R 15 is selected from hydrogen, halogen or C(1-6) alkyl. In some cases, R 15 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 15 is hydrogen. In some specific embodiments, R 11 and R 12 and R 14 and R 15 are each independently hydrogen, and R 13 is selected from fluorine, chlorine, bromine and iodine. In some specific embodiments, R 11 and R 12 and R 14 and R 15 are each independently hydrogen, and R 13 is chlorine.

[0261] In some embodiments, A is a 5-membered fused heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen or sulfur. In some cases, A is a 5-membered fused heteroaryl ring having two heteroatoms independently selected from nitrogen or oxygen. In some cases, A is a 5-membered fused heteroaryl ring having two heteroatoms selected from nitrogen and oxygen. In some cases, A is a 5-membered fused heteroaryl ring having two heteroatoms independently selected from nitrogen or sulfur. In some cases, A is a 5-membered fused heteroaryl ring having two heteroatoms selected from nitrogen and sulfur. In some specific cases, A is selected from thiazolo ring, isothiazolo ring, oxazolo ring, isoxazolo ring, pyrazolo ring and imidazolo ring. In some specific cases, A is isothiazolo.

[0262] In some embodiments, A is a 5- to 6-membered fused heteroaryl ring having 1 to 3 heteroatoms independently selected from benzofused, or nitrogen, oxygen or sulfur. In some cases, A is a 5-membered fused heteroaryl ring having 2 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur or a 6-membered fused heteroaryl ring having 2 to 3 nitrogen atoms. In some cases, A is benzofused. In some embodiments, A is a 5- to 6-membered fused heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some cases, A is a 6-membered fused heteroaryl ring having 1 to 3 nitrogen atoms. In some specific cases, A is selected from a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring and a triazine ring. In some specific cases, A is a 5-membered fused heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen or sulfur. In some specific cases, A is thieno. In some specific cases, A is furo. In some specific cases, A is pyrrolo.

[0263] In some embodiments, R 4 is -R, halogen, -OR, -SR, -N(R') 2 , -CN, -NO 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(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 wherein R and R' are as defined and described herein. In some embodiments, R 4 is -R. In some specific embodiments, R 4 is hydrogen. In some other specific embodiments, R 4 is halogen. In some embodiments, R 4 is -OR, -SR or -N(R') 2 -. In some specific cases, R 4 is -OR. In some specific cases, R 4 is -CN or -NO 2 . In some specific cases, R 4 is -C(O)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 or -C(S)OR. In some specific cases, R 4 is -S(O)R, -SO 2 R or -SO 2 N(R') 2 . In some specific cases, R 4 is -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(R') 2 , -N(R')N(R') 2 or -N(R')C(=N(R'))N(R') 2 . In some specific cases, R 4 is -C=NN(R') 2 , -C=NOR, -C(=N(R'))N(R') 2 . In some specific cases, R 4 is -OC(O)R or -OC(O)N(R') 2 .

[0264] In some embodiments, m is an integer from 0 to 5. In some cases, m is 1. In some cases, m is 2. In some cases, m is 3. In some cases, m is 4. In some specific cases, m is 5.

[0265] In some embodiments, each R 1 is independently selected from hydrogen and C(1-6) alkyl. In some cases, each R 1 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, each R 1 is independently selected from C(1-6) aliphatic, -OR, -N(R') 2 , -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR' or -CO 2 R. In some cases, each R 1 is hydrogen or C(1-6) alkyl. In some cases, each R 1 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, each R 1 is methyl.

[0266] In some embodiments, each R 2 is independently selected from hydrogen and C(1-6) alkyl. In some cases, each R 2 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, each R 2 is independently selected from C(1-6) aliphatic, -OR, -N(R') 2 , -C(O)R, -OC(O)R, -N(R')C(O)R, -C(O)NR' or -CO 2 R. In some cases, each R 2 is hydrogen or C(1-6) alkyl. In some cases, each R 2is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, each R 2 is methyl.

[0267] In some specific embodiments, n is an integer from 1 to 4; R 1 and R 2 each independently is selected from hydrogen and C(1-6) alkyl. In some specific cases, n is an integer from 1 to 4, and R 1 and R 2 each independently is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, n is an integer from 1 to 4, and R 1 and R 2 each is methyl. In some specific cases, n is 1, and R 1 and R 2 each is hydrogen. In some specific cases, n is 1, and R 1 and R 2 each is methyl.

[0268] In some embodiments, Z is -CH 2 . In some cases, Z is -NH. In some cases, Z is -O-. In some cases, Z is -S-.

[0269] In some specific embodiments, the bromodomain-containing 4 ligand (BR) is a compound as described in International Patent Application Publication No. WO2012 / 075456, the disclosure of which is incorporated by reference.

[0270] In some specific embodiments, the bromodomain-containing 4 ligand (BR) is TIFF2025517099000099.tif37128 wherein TIFF2025517099000100.tif2128 represents a bond to a linker selected from.

[0271] In some particular embodiments, the bromodomain-containing 4 ligand (BR) has the formula IA5: TIFF2025517099000101.tif37128wherein TIFF2025517099000102.tif2128represents a bond with a linker and is as follows.

[0272] In some particular embodiments, the bromodomain-containing 4 ligand (BR) is TIFF2025517099000103.tif38128wherein TIFF2025517099000104.tif2128represents a bond with a linker and is selected from

[0273] In some particular embodiments, the bromodomain-containing 4 ligand (BR) is TIFF2025517099000105.tif68128wherein TIFF2025517099000106.tif2128represents a bond with a linker and is selected from

[0274] In some particular embodiments, the bromodomain-containing 4 ligand (BR) is TIFF2025517099000107.tif109146TIFF2025517099000108.tif205146and is selected from

[0275] In some cases, the ligand is JQ1.

[0276] EL: Ligand for estrogen receptor A method of treating a subject for diffuse large B-cell lymphoma (DLBCL) is provided. In some cases, the method may include administering a proximity chemical inducer (CIP) to treat the subject for DLBCL. Also provided are compositions that have been found to be useful in the practice of the methods of the present disclosure.

[0277] The CIPs used in aspects of the present disclosure include ligands for oncogenic transcription factors, such as estrogen receptors. This aspect is particularly important in the treatment of cancer, where the CIP causes the suicide of cancer cells by their own drivers. An oncogenic transcription factor is a transcription factor whose activity contributes to a neoplastic, such as a cancerous, disease state. Oncogenic transcription factors can vary, for example, depending on the specific nature of the disease state being treated, and examples of oncogenic transcription factors include, but are not limited to, hormone receptors (such as estrogen receptors, androgen receptors, and progesterone receptors), cancer gene drivers (such as MYC, MLL fusion proteins, ETS fusion proteins, SS18-SSX fusion proteins), translocation-type fusion cancer genes, and proteins that regulate cell cycle entry (such as E2F family members). In some cases, the oncogenic transcription factor is a hormone receptor. Hormone receptors that can be used as oncogenic transcription factors in aspects of the present disclosure include, but are not limited to, estrogen receptors (ER). Any convenient ligand for such a hormone receptor can be used, where suitable ligands include small molecule ligands that have the ability to specifically bind to the target hormone receptor without any associated negative effect by the CIP on the transcriptional activation activity of the target hormone receptor, i.e., the ability to enhance the transcription of target apoptosis-promoting genes by the target hormone receptor when complexed with an anchor transcription factor. The molecular weight of such ligands can vary, and in some cases, it is in the range of 150 daltons to 500 daltons, such as 250 daltons to 400 daltons. Suitable ligands for estrogen receptors include, but are not limited to, TIFF2025517099000109.tif110165.

[0278] In some cases, the ligand is estrone.

[0279] CDK ligand Provided are methods of treating a subject for a malignant tumor, such as lymphoma (e.g., DLBCL), lung cancer (e.g., SCLC), breast cancer, etc. In some cases, the method may include administering a transcription-based proximity chemical inducer (TCIP) that links a BTB-domain-containing protein, such as BCL-6 or a related family member, and a cyclin-dependent kinase (CDK) to treat the subject for the malignant tumor. Also provided are compositions found to be useful in the practice of the methods of the present disclosure.

[0280] The TCIP used in aspects of the present disclosure may include a ligand for a transcription regulator, such as a CDK, such as CDK9, CDK8, CDK12, or CDK7. This aspect is particularly important in the treatment of cancer, where the CIP causes apoptosis of cancer cells by its CDK driver. Any convenient CDK ligand may be used, where suitable ligands include the ability to enhance the transcription of a target apoptotic-promoting gene by the target CDK when complexed with an anchor transcription factor, i.e., the transcriptional activation activity of the CDK, without any associated negative effect by the TCIP, and the ability to specifically bind to the target CDK. Small molecule ligands having such an ability may be mentioned. The molecular weight of such ligands can vary, and in some cases, it is in the range of 150 daltons to 500 daltons, such as 250 daltons to 400 daltons.

[0281] In some cases, the CDK is CDK9. Suitable ligands for CDK9 include, but are not limited to, those described in PCT application publications: WO / 2022 / 098843; WO / 2022 / 028556; WO / 2021 / 260578; WO / 2021 / 227904; WO / 2021 / 172359; WO / 2020 / 259556; WO / 2020 / 244612; WO / 2020 / 228513; WO / 2020 / 202232; WO / 2020 / 117988; WO / 2020 / 092314; WO / 2019 / 242471; WO / 2019 / 209825; WO / 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 incorporated herein by reference.

[0282] Specific CDK9 ligands of interest include, but are not limited to, TIFF2025517099000110.tif103146TIFF2025517099000111.tif191146TIFF2025517099000112.tif244146.

[0283] In some cases, the CDK is CDK8. Suitable ligands for CDK8 include, but are not limited to, those described in PCT application publication: WO / 2021 / 108581; WO / 2020 / 071550; WO / 2020 / 027704; WO / 2019 / 068613; WO / 2019 / 031990; WO / 2018 / 156858; WO / 2018 / 136202; WO / 2018 / 027082; WO / 2017 / 202719; WO / 2017 / 185034; WO / 2017 / 091836; WO / 2016 / 100782; WO / 2016 / 009076; WO / 2015 / 049325; WO / 2014 / 194245; WO / 2014 / 194201; WO / 2014 / 134169; WO / 2013 / 122609; WO / 2013 / 116786; and WO / 2013 / 001310; the disclosures of which are incorporated herein by reference.

[0284] Specific CDK8 ligands of interest include, but are not limited to, TIFF2025517099000113.tif88128TIFF2025517099000114.tif210120.

[0285] In some cases, the CDK is CDK7. Suitable ligands for CDK7 include, but are not limited to, the published PCT applications: WO / 2022 / 136174; WO / 2022 / 084930; WO / 2022 / 082056; WO / 2022 / 064009; WO / 2022 / 061155; WO / 2022 / 017533; WO / 2021 / 242602; WO / 2021 / 182914; WO / 2021 / 087138; WO / 2020 / 186196; WO / 2020 / 093006; WO / 2020 / 093011; WO / 2019 / 143730; WO / 2019 / 143719; WO / 2019 / 099298; WO / 2018 / 231859; WO / 2018 / 187357; WO / 2018 / 013867; WO / 2017 / 160797; WO / 2016 / 105528; WO / 2016 / 058544; WO / 2015 / 154022; WO / 2015 / 154038; WO / 2015 / 154039; WO / 2015 / 058140; and WO / 2014 / 063068; the disclosures of which are incorporated herein by reference.

[0286] Specific CDK7 ligands of interest include, but are not limited to, TIFF2025517099000115.tif127146TIFF2025517099000116.tif142146TIFF2025517099000117.tif161146TIFF2025517099000118.tif106146.

[0287] AR ligand Provided is a method of treating a subject for a malignant tumor, such as prostate cancer. In some cases, the method can include administering a transcriptional proximity chemical inducer (TCIP) that links a BTB-domain-containing protein, such as BCL-6 or a related family member, and an androgen receptor (AR) to treat the subject for the malignant tumor. Also provided are compositions useful in the practice of the methods of the disclosure and procedures for the selection of a population of sensitive patients.

[0288] The TCIPs used in the aspects of the present disclosure may include transcriptional modulators, such as oncogenic transcription factors, such as ligands of AR. This aspect is particularly important in the treatment of cancer, where the CIP causes apoptosis of cancer cells by their own drivers. An oncogenic transcription factor is a transcription factor whose activity contributes to a neoplastic, such as a cancerous, disease state. Oncogenic transcription factors can be various, and examples of oncogenic transcription factors that can be used here include AR. Any convenient ligand of such an oncogenic transcription factor can be used, where suitable ligands include the ability to enhance the transcription of a target apoptosis-promoting gene by the target oncogenic transcription factor when complexed with an anchor transcription factor, that is, without any associated negative effect by the TCIP on the transcriptional activation activity of the oncogenic transcription factor, and having the ability to specifically bind to the target oncogenic transcription factor. The molecular weights of such ligands can be various, and in some cases, they are in the range of 150 Daltons to 500 Daltons, such as 250 Daltons to 400 Daltons.

[0289] Suitable ligands for AR include, but are not limited to, those described in U.S. Patent Nos. 11,358,938; 11,332,465; 11,242,324; 11,185,549; 10,934,271; 10,815,221; 10,766,875; 10,662,148; 10,556,882; 10,526,310; 10,434,075; 10,308,630; 10,150,739; 10,053,418; 9,994,545; 9,969,683; 9,889,110; 9,884,038; 9,744,149; 9,963,433; 9,622,992; 9,611,225; 9,604,916; 9,481,663; 9,359,285; 9,340,524; 9,085,539; 9,809,583; 8,865,918; 8,802,689; 8,580,811; 8,519,158; 8,445,507; 8,420,694; 8,193,357; 8,183,388; 7,816,372; 7,727,980; 7,365,202; 7,288,553; 7,214,690; 7,026,484; 6,960,474; 6,534,516; 6,462,038; 6,017,924; and 5,677,336; the disclosures of which are hereby incorporated by reference herein.

[0290] Suitable ligands for AR include, but are not limited to, AR agonists, such as steroidal AR agonists, such as, but not limited to, TIFF2025517099000119.tif36128.

[0291] non-steroidal AR agonists, such as, but not limited to, TIFF2025517099000120.tif68128 are also of interest.

[0292] In some cases, the AR ligand is an AR antagonist, such as a non-steroidal AR antagonist, where examples of non-steroidal AR antagonists include, but are not limited to, TIFF2025517099000121.tif16128.

[0293] In some cases, the AR antagonist is a steroidal AR antagonist, where examples of steroidal AR antagonists include, but are not limited to, TIFF2025517099000122.tif30128.

[0294] Anchor transcription factor ligand The method of any one example of the present disclosure involves supplying, into a cell, a transcription-based proximity chemical inducer (TCIP) that links a first endogenous anchor transcription factor, such as BCL-6 (and / or its functional homolog, Table 3), which binds to the promoter of an apoptosis-promoting gene, and a second endogenous transcription modulation factor, such as ER, CDK, BRD4, AR, etc., for example, by a protocol such as those described below. Here, due to the CIP-mediated linkage of these factors, the transcription of the apoptosis-promoting gene in the cell is enhanced. In some cases, the TCIP used in such a manner is generally as described above and includes a first ligand that specifically binds to an anchor transcription factor, such as BCL-6, and a second ligand that specifically binds to a transcription modulation factor, such as ER, BRD4, CDK9, AR. Here, these first and second ligands are linked by binding or by a suitable linker, such as those described below.

[0295] A variety of different anchor transcription factors can be used in a method of this manner. Anchor transcription factors of interest include, but are not limited to, BCL-6, TFAP2A, TFAP2C, SP3, TFDP1, ELK3, SREBF1, SREBF2, THRA, SMAD2, TFDP1, TCF3, USF1, USF2, VEZF1, PBX1, HIF1A, RARA, FOXO3A, MAZ, E2F1, E2F2, PAX9, STAT1, SPDEF, CREB3L1, BATF, XBP1, SIX4, AR, LEF1, MYB, RUNX1, and PPARG. In some cases, the anchor transcription factor is BCL-6.

[0296] Of interest in some particular embodiments are BTB-domain-containing proteins, such as BCL-6 and related family members. Small molecules that bind to the BTB domain, such as BI3812 and others above, can effect their results by binding to either one or several of BCL6 and / or any of the 131 BTB-domain-containing proteins encoded in the human genome shown in the list of Table 3 below. Generally, such BTB-domain proteins also have a DNA-binding domain. This often allows for the activation of different biological programs in different cell types by TCIP due to their expression in a tissue-specific manner. In certain cancers, the selective expression of BTB-domain-containing proteins may, for example, result in the removal of repression by various epigenetic mechanisms, such as the removal of the polycomb repressive complex, the removal of the histone deacetylase complex, or other means to cause cell death. Also, recruitment to the loci occupied by BTB-domain-containing proteins may cause steric hindrance or other mechanisms to cause the death of cancer cells. Also, the recruitment of BTB-domain-containing proteins to form a ternary complex may result in a force with new activities that are therapeutically useful. For example, a cell-type-specific BTB-domain protein may prevent the binding of BRD4 to chromatin in a particular type of cancer cell, such as SCLC, thereby resulting in a tissue-specific inhibition of the action of BRD4.

[0297] The BTB domain-containing proteins that are BCL6 homologs, as shown in Table 3, include family members known to suppress cell death genes such as p53, Puma, Bim, etc. (doi:10.4049 / jimmunol.1600013; doi:10.4049 / jimmunol.1101451; doi:10.3389 / fimmu.2021.713294; dx.doi.org / 10.1016 / j.molcel.2014.02.017). The suppression of cell death genes is due to the binding of epigenetic repressors such as BCOR, SMRT, NCOR, etc. The BTB domain of this family is extremely important for this suppression, and point mutations near the corepressor binding site within the BTB domain relieve the suppression and result in abnormal cell death (doi:10.4049 / jimmunol.1600013). Since the BTB family has functional similarity to BCL6, ligands for its BTB domain are useful for constructing TCIPs similar to those described in this application with respect to BCL6.

[0298] (Table 3) BTB domain-containing proteins useful for the design and synthesis of CIP and TCIP TIFF2025517099000123.tif42128TIFF2025517099000124.tif255114

[0299] For TCIPs of such embodiments, any convenient ligand of such anchor transcription factors can be used, where suitable ligands include small molecule ligands having the ability to specifically bind to the target anchor transcription factor without any associated negative impact on the ability of the target anchor transcription factor to bind to the target DNA binding site. The molecular weights of such ligands can vary, and in some cases are in the range of 50 Daltons to 1200 Daltons, such as 200 to 500 Daltons. Suitable ligands for the anchor transcription factor can be selected using any convenient protocol, such as an in silico screening protocol, for example, those described below.

[0300] When the anchor transcription factor is BCL-6, suitable 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 U.S. Patent Application Publication Nos. 20210330672; 20210206756; 20210163497; 20210147382; 20210053978; 20200331921; 20200325119; 20200308147; 20200071297; 20160166549; 20120014979; 20100130564; and 20090018083; the disclosures of which are incorporated herein by reference.

[0301] In some embodiments, the B cell lymphoma 6 ligand (BC) has the formula IB: TIFF2025517099000125.tif42128where: D is selected from bond, alkyl, amide, ester, carbamate, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino and substituted acylamino; E is -CH or nitrogen; G is nitrogen or CR 23 where R 23 is selected from hydrogen, -C(1-4)alkyl, -O-C(1-14)alkyl, -O-C(1-4)haloalkyl, -C(1-4)haloalkyl and halogen; J is -CH or nitrogen; M is -CH or nitrogen; K is -CH 2 , O, S or -NH; TIFF2025517099000126.tif2128 represents the binding to the linker; R 16 、R 17 、R 18 、R 19 、R 20 、R 21 R 22 Each of R 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 and is such.

[0302] In some cases, D is an amide. In some embodiments, D is an optionally substituted C(1-6) aliphatic. In some embodiments, D is a substituted type. In some embodiments, D is unsubstituted. In some specific embodiments, D is C(1-6) alkyl. In some specific embodiments, D is C(1-4) alkyl. In some specific embodiments, D is methyl, ethyl, propyl or isopropyl. In some cases, D is a divalent C(1-6) hydrocarbon chain in which one or two methylene units may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R'), -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 - and may be an optionally substituted divalent C(1-6) hydrocarbon chain. In some cases, D is a divalent C(1-6) hydrocarbon chain in which one methylene unit is -NR'-, -N(R')C(O)-, -C(O)N(R, -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2It may be replaced by - and may be a substituted divalent C(1-3) hydrocarbon chain. In some specific embodiments, D is such that one methylene unit is -NH-, -O-, -S-, -S(O)- or -SO 2 It is a C(1-3) hydrocarbon chain that may be replaced by -.

[0303] In some specific cases, E is nitrogen. In some specific cases, E is -CH.

[0304] In some cases, R 16 is selected from hydrogen, halogen or C(1-6) alkyl. In some cases, R 16 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 16 is hydrogen. In some specific cases, R 16 is halogen. In some cases, R 16 is selected from fluorine, chlorine, bromine and iodine. In some cases, R 16 is chlorine.

[0305] In some cases, R 17 is selected from hydrogen, halogen or C(1-6) alkyl. In some cases, R 17 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 17 is hydrogen. In some specific cases, R 17 is halogen. In some cases, R 17 is selected from fluorine, chlorine, bromine and iodine. In some cases, R 17 is chlorine. In some specific cases, R 16 is hydrogen and R 17 is chlorine.

[0306] In some embodiments, R 18is selected from hydrogen, -C(1-4)alkyl, -O-C(1-4)alkyl, and halogen. In some cases, R 18 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some cases, R 18 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy. In some cases, R 18 is an optionally substituted divalent C(1-6) hydrocarbon chain in which one or two methylene units may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R'), -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, or -SO 2 -. In some cases, R 18 is an optionally substituted divalent C(1-3) hydrocarbon chain in which one methylene unit may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R, -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, or -SO 2 -. In some specific embodiments, R 18 is a C(1-3) hydrocarbon chain in which one methylene unit may be replaced by -NH-, -O-, -S-, -S(O)-, or -SO 2 -. In some cases, R 18 is selected from fluorine, chlorine, bromine, and iodine.

[0307] In some cases, R 19 is selected from hydrogen, halogen, or C(1-6)alkyl. In some cases, R 19 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some specific cases, R 19 is hydrogen. In some specific cases, R19 is a halogen. In some cases, R 19 is selected from fluorine, chlorine, bromine, and iodine. In some cases, R 19 is chlorine. In some specific cases, R 16 is hydrogen, R 17 is chlorine, and R 19 is hydrogen.

[0308] In some embodiments, G is CR 23 and R 23 is selected from hydrogen, C(1-4) alkyl, -O-C(1-4) alkyl, -O-C(1-4) haloalkyl, and halogen. In some cases, R 23 is hydrogen, -C(1-4) alkyl, -O-C(1-4) alkyl, and halogen. In some cases, R 23 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some cases, R 23 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy. In some cases, R 23 is an optionally substituted divalent C(1-6) hydrocarbon chain in which one or two methylene units may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R'), -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, or -SO 2 -. In some cases, R 23 is an optionally substituted divalent C(1-3) hydrocarbon chain in which one methylene unit may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R, -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, or -SO 2 -. In some specific embodiments, R 23is a C(1-3) hydrocarbon chain in which one methylene unit may be replaced by -NH-, -O-, -S-, -S(O)- or -SO 2 -. In some cases, R 23 is selected from fluorine, chlorine, bromine and iodine.

[0309] In some cases, J is -CH. In some cases, J is nitrogen. In some cases, M is -CH. In some cases, M is nitrogen. In some cases, K is -CH 2 . In some cases, K is oxygen. In some cases, K is sulfur. In some cases, K is -NH.

[0310] In some embodiments, R 21 is hydrogen and -C(1-6) alkyl optionally substituted with one group selected from -OH, -NH 2 , -O-C 1~4 alkyl, -NH-C(1-4) alkyl, -N(C 1~4 alkyl) 2 , -C(3-6) cycloalkyl and 4-7 membered heterocyclyl, wherein each cycloalkyl and heterocyclyl group is optionally and independently substituted with one group selected from -C(1-3) alkyl, or R 21 is -C(3-6) cycloalkyl, 4-7 membered heterocyclyl, wherein each group may be substituted with one group selected from -C(1-3) alkyl. In some cases, R 21 is selected from -C(1-4) alkyl optionally substituted with one group selected from -OH, -C(3-6) cycloalkyl and -N(C 1~4 alkyl) 2 . In some embodiments, R 21 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -(CH2 ) 3 OH, -(CH 2 ) 2 (CH 3 ) 2 、 -CH 2 - cyclopropyl and -(CH 2 ) 2 N(CH 3 ) 2 selected from. In some cases, R 21 is hydrogen or C(1 - 6) alkyl. In some cases, R 21 is selected from methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl or tert - butyl. In some specific cases, R 21 is methyl.

[0311] In some embodiments, R 20 is selected from hydrogen, -C(1 - 4) alkyl, -O - C(1 - 4) alkyl and halogen. In some specific cases, R 20 is hydrogen. In some cases, R 20 is selected from methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl or tert - butyl. In some cases, R 20 is selected from methoxy, ethoxy, n - propoxy, isopropoxy, n - butoxy, isobutoxy or tert - butoxy. In some cases, R 20 is a divalent C(1 - 6) hydrocarbon chain which may be substituted and in which one or two methylene units may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -. In some cases, R 20 is a divalent C(1 - 6) hydrocarbon chain in which one methylene unit is replaced by -NR'-, -N(R')C(O)-, -C(O)N(R, -N(R')SO 2 -, -SO 2-N(R'), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 A divalent C(1-3) hydrocarbon chain, which may be replaced by - and may be substituted. In some specific embodiments, R 20 is a C(1-3) hydrocarbon chain in which one methylene unit may be replaced by -NH-, -O-, -S-, -S(O)- or -SO 2 -; In some cases, R 20 is selected from fluorine, chlorine, bromine and iodine.

[0312] In some embodiments, R 22 is -L 1 -C(R 24 R 25 )-R 26 or -CH=CH-R 26 where L 1 is -O- or -S-; R 24 is hydrogen or C(1-4) alkyl; R 25 is hydrogen or C(1-4) alkyl; or R 24 and R 25 together form -C(3-5) cycloalkyl; R 26 is -COOH, -CONH 2 , -C(O)R 27 , -C(O)OR 27 , -C(O)NR 27 R 28 , -S(O)-C 1-6 alkyl, -S(O) 2 -C(1-6) alkyl, -P(O)-(C 1-6 alkyl) 2 , -C(NH)NH 2 and R 27 is -OH, -CF 3 , -N(C 1~4 alkyl) 2 , -C(3-6) cycloalkyl, 3-6 membered heterocyclyl, -C(2-4) alkenyl, -C 2~4A 3- to 6-membered heterocyclyl or -C(1-4)alkyl, optionally substituted by one or more identical or different groups selected from alkynyl; R 28 is hydrogen or C(1-4)alkyl. In some specific cases, R 22 is selected from TIFF2025517099000127.tif174146.

[0313] In some embodiments, R 22 is TIFF2025517099000128.tif20128.

[0314] In some specific embodiments, B cell lymphoma 6 ligand (BC) is of formula IB1: TIFF2025517099000129.tif38128.

[0315] In some specific embodiments, B cell lymphoma 6 ligand (BC) is of formula IB2: TIFF2025517099000130.tif38128.

[0316] In some specific embodiments, B cell lymphoma 6 ligand (BC) is of formula IB3: TIFF2025517099000131.tif38128.

[0317] In some specific embodiments, B cell lymphoma 6 ligand (BC) is of formula IB4: TIFF2025517099000132.tif38128.

[0318] In some specific embodiments, B cell lymphoma 6 ligand (BC) is of formula IB5: TIFF2025517099000133.tif40128 wherein: D is selected from bonding, alkyl, amide, ester, carbamate, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino and substituted acylamino; E is -CH or nitrogen; G is nitrogen or CR 23 wherein, R 23 is selected from hydrogen, -C(1-4)alkyl, -O-C(1-14)alkyl, -O-C(1-4)haloalkyl, -C(1-4)haloalkyl and halogen; J is -CH or nitrogen; M is -CH or nitrogen; Q is -CH or nitrogen; K is -CH 2 , O, S or NH; TIFF2025517099000134.tif2128 represents the bond with the linker; R 16 , R 17 , R 18 , R 19 , R 20 and R 21 each independently is 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 of which.

[0319] In some cases, D is an amide. In some embodiments, D is an optionally substituted C(1-6) aliphatic. In some embodiments, D is substituted. In some embodiments, D is unsubstituted. In some specific embodiments, D is C(1-6) alkyl. In some specific embodiments, D is C(1-4) alkyl. In some specific embodiments, D is methyl, ethyl, propyl or isopropyl. In some cases, D is a divalent C(1-6) hydrocarbon chain in which one or two methylene units may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R'), -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -, and may be an optionally substituted divalent C(1-6) hydrocarbon chain. In some cases, D is a divalent C(1-6) hydrocarbon chain in which one methylene unit may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R, -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -, and may be an optionally substituted divalent C(1-3) hydrocarbon chain. In some specific embodiments, D is a C(1-3) hydrocarbon chain in which one methylene unit may be replaced by -NH-, -O-, -S-, -S(O)- or -SO 2 -.

[0320] In some specific cases, E is nitrogen. In some specific cases, E is -CH.

[0321] In some cases, R 16 is selected from hydrogen, halogen or C(1-6) alkyl. In some cases, R 16 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 16 is hydrogen. In some specific cases, R 16 is halogen. In some cases, R16 is selected from fluorine, chlorine, bromine and iodine. In some cases, R 16 is chlorine.

[0322] In some cases, R 17 is selected from hydrogen, halogen or C(1-6) alkyl. In some cases, R 17 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 17 is hydrogen. In some specific cases, R 17 is halogen. In some cases, R 17 is selected from fluorine, chlorine, bromine and iodine. In some cases, R 17 is chlorine. In some specific cases, R 16 is hydrogen and R 17 is chlorine.

[0323] In some embodiments, R 18 is selected from hydrogen, -C(1-4) alkyl, -O-C(1-4) alkyl and halogen. In some cases, R 18 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some cases, R 18 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. In some cases, R 18 is an optionally substituted divalent C(1-6) hydrocarbon chain in which one or two methylene units may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R'), -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -. In some cases, R 18 is an optionally substituted divalent C(1-6) hydrocarbon chain in which one methylene unit is replaced by -NR'-, -N(R')C(O)-, -C(O)N(R, -N(R')SO 2-, -SO 2 N(R'), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 - and may be replaced by, optionally substituted divalent C (1-3) hydrocarbon chain. In some specific embodiments, R 18 is a C (1-3) hydrocarbon chain in which one methylene unit may be replaced by -NH-, -O-, -S-, -S (O)- or -SO 2 -. In some cases, R 18 is selected from fluorine, chlorine, bromine and iodine.

[0324] In some cases, R 19 is selected from hydrogen, halogen or C (1-6) alkyl. In some cases, R 19 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 19 is hydrogen. In some specific cases, R 19 is halogen. In some cases, R 19 is selected from fluorine, chlorine, bromine and iodine. In some cases, R 19 is chlorine. In some specific cases, R 16 is hydrogen, R 17 is chlorine, R 19 is hydrogen.

[0325] In some embodiments, G is CR 23 and R 23 is selected from hydrogen, C (1-4) alkyl, -O-C (1-4) alkyl, -O-C (1-4) haloalkyl and halogen. In some cases, R 23 is hydrogen, -C (1-4) alkyl, -O-C (1-4) alkyl and halogen. In some cases, R 23 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some cases, R 23is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. In some cases, R 23 is a divalent C(1-6) hydrocarbon chain which may be substituted or unsubstituted, where one or two methylene units may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R'), -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -. In some cases, R 23 is a divalent C(1-3) hydrocarbon chain which may be substituted or unsubstituted, where one methylene unit may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R, -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -. In some specific embodiments, R 23 is a C(1-3) hydrocarbon chain which may be substituted or unsubstituted, where one methylene unit may be replaced by -NH-, -O-, -S-, -S(O)- or -SO 2 -. In some cases, R 23 is selected from fluorine, chlorine, bromine and iodine.

[0326] In some cases, J is -CH. In some cases, J is nitrogen. In some cases, M is -CH 2 . In some cases, M is nitrogen. In some cases, K is -CH

[0327] In some embodiments, R 20 is selected from hydrogen, -C(1-4)alkyl, -O-C(1-4)alkyl and halogen. In some specific cases, R 20 is hydrogen. In some cases, R 20is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some embodiments, R 20 is methyl. In some cases, R 20 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. In some cases, R 20 is a divalent C(1-6) hydrocarbon chain which may be substituted with one or two methylene units being -NR'-, -N(R')C(O)-, -C(O)N(R')-, -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -. In some cases, R 20 is a divalent C(1-3) hydrocarbon chain which may be substituted with one methylene unit being -NR'-, -N(R')C(O)-, -C(O)N(R, -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -. In some specific embodiments, R 20 is a C(1-3) hydrocarbon chain which may be substituted with one methylene unit being -NH-, -O-, -S-, -S(O)- or -SO 2 -. In some cases, R 20 is selected from fluorine, chlorine, bromine and iodine.

[0328] In some embodiments, R 21 is hydrogen and, -OH, -NH 2 , -O-C 1~4 alkyl, -NH-C(1-4)alkyl, -N(C 1~4 alkyl) 2selected from -C(1-6) alkyl optionally substituted with one group selected from -C(3-6) cycloalkyl and 4-7 membered heterocyclyl, wherein each cycloalkyl and heterocyclyl group is optionally and independently substituted with one group selected from -C(1-3) alkyl, or R 21 is -C(3-6) cycloalkyl, 4-7 membered heterocyclyl, wherein each group may be substituted with one group selected from -C(1-3) alkyl. In some cases, R 21 is selected from -OH, -C(3-6) cycloalkyl and -N(C 1~4 alkyl) 2 and is selected from -C(1-4) alkyl optionally substituted with one group selected therefrom. In some cases, R 21 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -(CH 2 ) 3 OH , -(CH 2 ) 2 (CH 3 ) 2 , -CH 2 -cyclopropyl and -(CH 2 ) 2 N(CH 3 ) 2 . In some specific embodiments, R 21 is TIFF2025517099000135.tif15128. In some cases, R 21 is selected from -OH, -C(3-6) cycloalkyl and -N(C 1~4 alkyl) 2 and is selected from -C(1-4) alkyl optionally substituted with one group selected therefrom. In some embodiments, R 21 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2CH 3 ,-CH(CH 3 ) 2 ,-(CH 2 ) 3 OH,-(CH 2 ) 2 (CH 3 ) 2 ,-CH 2 -cyclopropyl and -(CH 2 ) 2 N(CH 3 ) 2 is selected from. In some cases, R 21 is hydrogen or C(1-6) alkyl. In some cases, R 21 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 21 is methyl.

[0329] In some specific embodiments, B cell lymphoma 6 ligand (BC) has the formula IB6: TIFF2025517099000136.tif44128wherein TIFF2025517099000137.tif2128represents the bond to the linker is of that.

[0330] In some embodiments, B cell lymphoma 6 ligand (BC) has the formula IB7: TIFF2025517099000138.tif42128wherein: D is selected from bond, alkyl, amide, ester, carbamate, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino and substituted acylamino; E is -CH or nitrogen; G is nitrogen or CR 23 ,wherein, R 23 is selected from hydrogen, -C(1-4) alkyl, -O-C(1-14) alkyl, -O-C(1-4) haloalkyl, -C(1-4) haloalkyl and halogen; J is -CH or nitrogen; M is -CH or nitrogen; K is -CH 2 , O, S or NH; TIFF2025517099000139.tif2128 represents the bond with the linker; R 16 、R 17 、R 18 、R 19 and R 21 each independently is 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 is one of.

[0331] In some cases, D is an amide. In some embodiments, D is an optionally substituted C(1-6) aliphatic. In some embodiments, D is a substituted type. In some embodiments, D is unsubstituted. In some specific embodiments, D is C(1-6) alkyl. In some specific embodiments, D is C(1-4) alkyl. In some specific embodiments, D is methyl, ethyl, propyl or isopropyl. In some cases, D is a divalent C(1-6) hydrocarbon chain in which one or two methylene units may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R'), -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 - and is an optionally substituted divalent C(1-6) hydrocarbon chain. In some cases, D is a divalent C(1-6) hydrocarbon chain in which one methylene unit is -NR'-, -N(R')C(O)-, -C(O)N(R, -N(R')SO 2 -,-SO2 A divalent C(1-3) hydrocarbon chain optionally replaced by -N(R'), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 - and optionally substituted. In some specific embodiments, D is a C(1-3) hydrocarbon chain in which one methylene unit is optionally replaced by -NH-, -O-, -S-, -S(O)- or -SO 2 -.

[0332] In some specific cases, E is nitrogen. In some specific cases, E is -CH

[0333] In some cases, R 16 is selected from hydrogen, halogen or C(1-6) alkyl. In some cases, R 16 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 16 is hydrogen. In some specific cases, R 16 is halogen. In some cases, R 16 is selected from fluorine, chlorine, bromine and iodine. In some cases, R 16 is chlorine.

[0334] In some cases, R 17 is selected from hydrogen, halogen or C(1-6) alkyl. In some cases, R 17 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some specific cases, R 17 is hydrogen. In some specific cases, R 17 is halogen. In some cases, R 17 is selected from fluorine, chlorine, bromine and iodine. In some cases, R 17 is chlorine. In some specific cases, R 16 is hydrogen and R 17 is chlorine.

[0335] In some embodiments, R 18 is selected from hydrogen, -C(1-4)alkyl, -O-C(1-4)alkyl, and halogen. In some cases, R 18 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some cases, R 18 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy. In some cases, R 18 is an optionally substituted divalent C(1-6) hydrocarbon chain in which one or two methylene units may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R'), -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, or -SO 2 -. In some cases, R 18 is an optionally substituted divalent C(1-3) hydrocarbon chain in which one methylene unit may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R), -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, or -SO 2 -. In some specific embodiments, R 18 is a C(1-3) hydrocarbon chain in which one methylene unit may be replaced by -NH-, -O-, -S-, -S(O)-, or -SO 2 -. In some cases, R 18 is selected from fluorine, chlorine, bromine, and iodine.

[0336] In some cases, R 19 is selected from hydrogen, halogen, or C(1-6)alkyl. In some cases, R 19 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some specific cases, R19 is hydrogen. In some specific cases, R 19 is a halogen. In some cases, R 19 is selected from fluorine, chlorine, bromine, and iodine. In some cases, R 19 is chlorine. In some specific cases, R 16 is hydrogen, R 17 is chlorine, and R 19 is hydrogen.

[0337] In some embodiments, G is CR 23 and R 23 is selected from hydrogen, C(1-4)alkyl, -O-C(1-4)alkyl, -O-C(1-4)haloalkyl, and halogen. In some cases, R 23 is hydrogen, -C(1-4)alkyl, -O-C(1-4)alkyl, and halogen. In some cases, R 23 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some cases, R 23 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy. In some cases, R 23 is an optionally substituted divalent C(1-6)hydrocarbon chain in which one or two methylene units may be replaced by -NR'-, -N(R')C(O)-, -C(O)N(R'), -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, or -SO 2 -. In some cases, R 23 is an optionally substituted divalent C(1-6)hydrocarbon chain in which one methylene unit is replaced by -NR'-, -N(R')C(O)-, -C(O)N(R, -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, or -SO 2It may be replaced by - and may be a substituted divalent C(1-3) hydrocarbon chain. In some specific embodiments, R 23 is a C(1-3) hydrocarbon chain in which one methylene unit may be replaced by -NH-, -O-, -S-, -S(O)- or -SO 2 -. In some cases, R 23 is selected from fluorine, chlorine, bromine and iodine.

[0338] In some cases, J is -CH. In some cases, J is nitrogen. In some cases, M is -CH. In some cases, M is nitrogen. In some cases, K is -CH 2 . In some cases, K is oxygen. In some cases, K is sulfur. In some cases, K is -NH.

[0339] In some embodiments, R 21 is selected from hydrogen and -C(1-6) alkyl optionally substituted with one group selected from -OH, -NH 2 , -O-C 1~4 alkyl, -NH-C(1-4) alkyl, -N(C 1~4 alkyl) 2 , -C(3-6) cycloalkyl and 4-7 membered heterocyclyl, wherein each cycloalkyl and heterocyclyl group is optionally and independently substituted with one group selected from -C(1-3) alkyl, or R 21 is -C(3-6) cycloalkyl, 4-7 membered heterocy...

Claims

1. A proximity chemoinducer (CIP) for use in a method of treatment of the subject, having a B-cell lymphoma 6 (BCL-6) ligand covalently bound to either (a) a bromodomain and extraterminal domain (BET) family protein ligand or (b) a cyclin-dependent kinase (CDK) ligand, wherein the method comprises the step of regulating the expression of a target gene in a cell, (i) The BCL-6 ligand exhibits specific binding to an endogenous BCL-6 protein that binds to a target gene, or to a region near the target gene such as a promoter or regulatory region, (ii) The (a) BET family protein ligand or (b) CDK ligand exhibits specific binding to (a) endogenous BET protein or (b) endogenous CDK protein, (iii) Based on contact between the cell and the CIP, the BCL-6 protein and the (a) BET protein or (b) CDK protein spatially complex together via the CIP, thereby acquiring function in the cell. Proximity chemical inductants (CIPs).

2. An in vitro method for regulating the expression of a target gene in a cell using a proximity chemoinducer (CIP) having a B-cell lymphoma 6 (BCL-6) ligand covalently bound to either (a) a bromodomain and an extraterminal domain (BET) family protein ligand or (b) a cyclin-dependent kinase (CDK) ligand, (i) The BCL-6 ligand exhibits specific binding to an endogenous BCL-6 protein that binds to a target gene, or to a region near the target gene such as a promoter or regulatory region, (ii) The (a) BET family protein ligand or (b) CDK ligand exhibits specific binding to (a) endogenous BET protein or (b) endogenous CDK protein, (iii) Based on contact between the cell and the CIP, the BCL-6 protein and the (a) BET protein or (b) CDK protein spatially complex together via the CIP, thereby acquiring function in the cell. method.

3. (i) The gain of function modulates the expression of the target gene in a manner dependent on the presence of a BET family protein bound to the CIP, or (ii) The acquisition of function is characterized in that it modulates the expression of the target gene in a manner that is dependent on the presence of the CDK bound to the CIP, A proximity chemical inducer (CIP) for use according to claim 1.

4. (i) The acquisition of function is achieved by utilizing less than 50% of the amount of (a) endogenous BET protein or (b) endogenous CDK protein present in the cell, or (ii) The CIP mediates the acquisition of the function at an EC of less than 1 micromol, or (iii) The expression of the target gene is modulated in less than approximately 16 hours or approximately 16 hours after contact. CIP for use according to claim 3.

5. The CIP is AB (Formula I), or A-Linker-B (Formula II) It is a compound containing the structure, A contains a BCL-6 ligand, B contains a BET family protein ligand or a CDK ligand. CIP for use according to claim 1, 3, or 4, or the method according to claim 2.

6. The CIP for use according to any one of claims 1 or 3 to 5, or the method according to claim 2, wherein the BET family protein is BRD4.

7. The target gene is an apoptosis-promoting gene, The method includes a step of increasing the expression of apoptosis-promoting genes within the cells, The above method results in the death of the cells, Optionally, the apoptosis-promoting gene is selected from the group consisting of TP53, PUMA (BBC3), BIM (BCL2L11), BID, BAX, BAK, BOK, BAD, HRK, BIK, BMF, NOXA, CASP8, and CASP10. CIP for use according to any one of claims 1 or 3 to 6, or the method according to claim 2.

8. The cells are diseased cells, Optionally, the lesioned cells overexpress both BCL-6 and BET family proteins, or both BCL-6 and CDK, compared to non-lesioned cells. Optionally, if the lesion cells are cancer cells, CIP for use according to any one of claims 1 or 3 to 7, or the method according to claim 2.

9. The CIP for use according to claim 1 or any one of claims 3 to 8 dependent on claim 1, wherein the subject is a human.

10. The CIP for use according to claim 9, wherein the subject has a disease, disorder, or condition, and the administration of the CIP treats the disease, disorder, or condition, or symptoms associated therewith.

11. The disease, disorder, or condition is a malignant tumor, Optionally, the malignant tumor is small cell lung cancer (SCLC), diffuse large B-cell lymphoma (DLBCL), breast cancer, or a malignant tumor with high levels of BCL-6 protein expression. Optionally, if the DLBCL is refractory DLBCL, Optionally, the DLBCL is a CHOP-resistant DLBCL. Optionally, if the malignant tumor is a mutation in TP53, CIP for use according to claim 10.

12. B-cell lymphoma 6 (BCL-6) and a proximal chemoinducer (CIP) conjugated to either (a) a bromodomain and extraterminal domain (BET) family protein or (b) a cyclin-dependent kinase (CDK) for use as a drug.

13. B-cell lymphoma 6 (BCL-6) for use in the treatment of malignant tumors, and a proximal chemoinducer (CIP) conjugated to either (a) a bromodomain and extraterminal domain (BET) family protein or (b) a cyclin-dependent kinase (CDK).

14. AB (Formula I), or A-Linker-B (Formula II) A proximity chemical inducer (CIP) having the structure, A includes a first portion that exhibits selective binding to B-cell lymphoma 6 (BCL-6), B, (a) Bromodomain and extraterminal domain (BET) family proteins, or (b) Cyclin-dependent kinase (CDK) A second part showing a selective binding to any of the following: Proximity chemical inductants (CIPs).

15. The CDK is selected from the group consisting of CDK9, CDK8, and CDK7, or The BET family protein is selected from the group consisting of BRD4, BRD2, BRD3, BRD5, BRD7, BRD9, and BRDT. A CIP for use according to any one of claims 1, 3 to 5, or 7 to 13, or the method according to claim 2, or the CIP according to claim 14.

Images