BET inhibitors for the treatment of cancer

Abstract

Provided herein are methods of treating a cancer comprising a loss of function or a deletion of an EP300 gene or a portion thereof using a BET inhibitor.

Description

[0001] Cross-referencing This application claims the benefit of U.S. Provisional Application No. 63 / 581,241, filed September 7, 2023, and U.S. Provisional Application No. 63 / 625,852, filed January 26, 2024, the contents of which are incorporated herein by reference. Background Technology

[0002] BET inhibitors are a class of drugs that target a family of proteins called bromodomain and extra-terminal (BET) proteins. These proteins play crucial roles in regulating gene expression and chromatin structure, cell cycle progression, and other important cell biological functions. Their involvement in cell growth and differentiation makes them potentially significant in the pathophysiology of cancer. Among many different mechanisms of action, BET inhibitors can disrupt the interaction between BET proteins and chromatin, leading to changes in gene expression, thereby inhibiting the growth and survival of cancer cells. Despite showing promise in some studies, the lack of clinical efficacy, dose-limiting toxicities, and widespread resistance to BET inhibitors remain significant challenges. Therefore, there is a need to develop novel BET inhibitor therapies for targeted cancer treatment. Summary of the Invention

[0003] This disclosure is based in part on the finding that cancer can be associated with loss or absence of function of the EP300 gene, and that, once identified, such cancers can be treated by administering (e.g., a therapeutically effective amount) a pharmaceutical composition containing a bromine domain and an extra-terminal (BET) inhibitor.

[0004] In some embodiments, this document provides a method for treating cancer in a subject of need, the method comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a bromodomain and extra-terminal domain (BET) inhibitor; the cancer has been previously identified as involving loss of function or deletion of the EP300 gene; and the patient is not concurrently receiving (Compound 1) or (Compound 2), and When the cancer is triple-negative breast cancer, the BET inhibitor is not JQ1.

[0005] In some embodiments, this document provides a method for treating cancer in a subject of need, the method comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a bromine domain and an additional terminal domain (BET) inhibitor; the cancer has been previously identified as containing a reduced amount or activity of p300 compared to wild-type p300; and the patient is not concurrently receiving (Compound 1) or (Compound 2), and When the cancer is triple-negative breast cancer, the BET inhibitor is not JQ1. In some embodiments, the loss of function is caused by a genetic mutation. In some embodiments, the subject has not previously received compound 1 or compound 2. In some embodiments, the BET inhibitor includes ABBV-075, ABBV-744, apabetalone, APL-581, ARV-825, AZD-5153, BI-6727, BI-894999, BMS-986158, BOS-475, BPI-23314, CD-161, CG-223, CK-103, CN- 470, FT-1101, GNE-0011, GS-5829, GS-626510, GSK525762, I-BET151, INCB054329, INCB576 43. JQ1, LY-294002, NEO2734, ODM-207, OMT-001, OMT-002, OTX-015, Pelabresib, PLX-2853 (OPN-2853), PLX-51107 (OPN-51107), TEN-010, RVX-297, SRX-2523, SRX-3225, SRX-3254, SW-064652, SYHA-1801, TTI-281, Zen-3694, CPI-0610, INCB0543294, INCB057643, CC-90010, Alobresib, GSK778, GSK046, Mivebresib, Trotabresib, Molibresib, Pelabresib, or combinations thereof. In some embodiments, the BET inhibitor includes AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, INCB57643, OTX-015, PLX-51107, or combinations thereof. In some embodiments, the BET inhibitor includes AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, OTX-015, PLX-51107, INCB057643, TEN-010, CC-90010, arobuxare, ODM-207, GSK778, GSK046, ABBV-744, mivebuxare, trotabresib, molibresib, birabresib, pelabresib, or combinations thereof.

[0006] In some embodiments, the BET inhibitor comprises a compound of formula (I): Or its pharmaceutically acceptable salts, tautomers, stereoisomers, or deuterated analogs, wherein: R 1 X is a cyano, halogenated, or optionally substituted with one to three (C1-C3) alkyl groups independently selected from halogenated, methyl, ethyl, methoxy, and ethoxy groups; and when present, X is halogenated. In some embodiments, R 1 It is (C1-C2) alkyl, cyano, or fluorine. In some embodiments, R 1 It is methyl. In some embodiments, R 1 It is fluorine. In some implementations, R 1 It is a cyano group.

[0007] In some embodiments, the BET inhibitor comprises a compound of formula (II): Or its pharmaceutically acceptable salts, tautomers, stereoisomers, or deuterated analogs, wherein: R 1 It is an (C1-C3) alkyl group optionally substituted with 1 to 3 substituents independently selected from halogenated, methyl, ethyl, methoxy, and ethoxy groups. In some embodiments, R 1 It is a methyl group.

[0008] In some embodiments, the BET inhibitor comprises a compound of formula (III): Or a pharmaceutically acceptable salt thereof, wherein: X is halogenated when present.

[0009] In some embodiments, the BET inhibitor comprises compound 3: (Compound 3), or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analog thereof. In some embodiments, the BET inhibitor comprises a compound having the formula (Va): Or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analogue thereof, wherein: R 2 It is H; R 4 It is H; R 6 It is H; R 7 It is H, -OH, C 1-6 Alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; R 1 It is optional to be 1-3 R j Group-substituted heteroaryl groups; each R jIndependently selected from halogen, -CN, -OH, -NH2, -NO2, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -CH=C(R k )(R k )、-OR k 、-SR k 、-OC(O)R k 、-OC(S)R k 、-P(=O)HR k 、-P(=O)R k R k 、-PH(=O)OR k 、-P(=O)(OR k )2、-OP(=O)(OR k )2、-C(O)H、-O(CO)OR k 、-C(O)R k 、-C(S)R k 、-C(O)OR k 、-C(S)OR k 、-S(O)R k 、-S(O)2R k 、-C(O)NHR k 、-C(S)NHR k 、-C(O)NR k R k 、-C(S)NR k R k 、-S(O)2NHR k 、-S(O)2NR k R k 、-C(NH)N HR k 、-C(NH)NR k R k 、-NHC(O)R k 、-NHC(S)R k 、-NR k C(O)R k 、-NR k C(S)R k 、-NHS(O)2R k 、-NR k S(O)2R k 、-NHC(O)NHR k 、-NHC(S)NHR k 、-NR k C(O)NH2、-NRk C(S)NH2、-NR k C(O)NHR k -NR k C(S)NHR k -NHC(O)NR k R k -NHC(S)NR k R k -NR k C(O)NR k R k -NR k C(S)NR k R k -NHS(O)2NHR k -NR k S(O)2NH2、-NR k S(O)2NHR k -NHS(O)2NR k R k -NR k S(O)2NR k R k -NHR k or -NR k R k ; Each R k H and C independently 1-6 Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, or cycloalkylalkyl; or when attached to the same carbon or nitrogen atom, two R k The groups together form a 3- to 6-membered carbon ring or a 3- to 8-membered heterocycle having 1-2 heteroatoms selected from O, N, or S as ring members, wherein the nitrogen or sulfur ring atom is optionally oxidized; R 3 It is H, halogen, -CN, or optionally substituted C. 1-6 Alkyl groups, optionally substituted deuterated C 1-6 Alkyl, optionally substituted aryl, optionally substituted aryl-C 1-4 Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-C 1-4 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 cycloalkyl-C 1-4 Alkyl, optionally substituted heterocyclic alkyl, or optionally substituted heterocyclic alkyl-C 1-4 Alkyl; and R 5 It is optionally selected by one or two independent factors chosen from D, halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4R of halogenated alkoxy or -CN 11 Group substitution The wavy line indicates the connection point with the rest of the molecule. In some embodiments, the BET inhibitor comprises compound 4: (Compound 4), or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

[0010] In some embodiments, the BET inhibitor comprises compound 9: (Compound 9) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof. In some embodiments, the cancer includes bladder cancer, lung cancer, gynecological cancer, adrenocortical carcinoma, bone cancer, central nervous system (CNS) cancer, pancreatic cancer, gastrointestinal cancer, head and neck cancer, skin cancer, mesothelioma, schwannoma, lymphoma, renal cell carcinoma, salivary gland cancer, non-melanoma skin cancer, or combinations thereof. In some embodiments, the cancer includes lung cancer. In some embodiments, the lung cancer includes non-small cell lung cancer. In some embodiments, the non-small cell lung cancer includes squamous cell carcinoma, large cell carcinoma, adenocarcinoma, or combinations thereof. In some embodiments, the non-small cell lung cancer includes squamous cell carcinoma. In some embodiments, the non-small cell lung cancer includes large cell carcinoma. In some embodiments, the non-small cell lung cancer includes adenocarcinoma. In some embodiments, the lung cancer includes small cell lung cancer. In some embodiments, the BET inhibitor comprises AZD-5153, INCB57643, OTX-015, PLX-51107, or combinations thereof. In some embodiments, the cancer includes bladder cancer. In some embodiments, the bladder cancer includes carcinoma. In some embodiments, the carcinoma includes urothelial carcinoma. In some embodiments, the BET inhibitor comprises AZD-5153, BMS-986158, GSK525762, INCB57643, OTX-015, PLX-51107, or combinations thereof. In some embodiments, the cancer includes pancreatic cancer. In some embodiments, the BET inhibitor comprises BI-894999, BMS-986158, GSK525762, INCB054329, INCB57643, OTX-015, PLX-51107, or combinations thereof. In some embodiments, the skin cancer includes melanoma. In some embodiments, the CNS cancer includes glioma. In some embodiments, the CNS cancer includes neuroepithelial tumors. In some embodiments, the lymphoma includes non-Hodgkin's lymphoma. In some embodiments, the lymphoma includes diffuse large B-cell lymphoma. In some embodiments, the lymphoma includes follicular lymphoma. In some embodiments, the lymphoma includes marginal zone lymphoma. In some embodiments, the lymphoma includes mature B-cell tumors. In some embodiments, the gastrointestinal cancer includes gastrointestinal stromal tumors, esophageal gastric cancer, gastrointestinal neuroendocrine tumors, small bowel cancer, anal cancer, colon cancer, or combinations thereof. In some embodiments, the gastrointestinal cancer includes gastrointestinal stromal tumors. In some embodiments, the gastrointestinal cancer includes esophageal gastric cancer. In some embodiments, the gastrointestinal cancer includes gastrointestinal neuroendocrine tumors. In some embodiments, the gastrointestinal cancer includes small bowel cancer. In some embodiments, the gastrointestinal cancer includes anal cancer. In some embodiments, the gastrointestinal cancer includes colon cancer.In some embodiments, the colon cancer includes colorectal cancer. In some embodiments, the gynecological cancer includes cervical cancer. In some embodiments, the gynecological cancer includes ovarian cancer. In some embodiments, the gynecological cancer includes sex cord-stromal tumors. In some embodiments, the gynecological cancer includes vaginal cancer. In some embodiments, the cancer includes uterine cancer. In some embodiments, the uterine cancer includes endometrial cancer or uterine sarcoma. In some embodiments, the uterine cancer includes endometrial cancer. In some embodiments, the endometrial cancer includes endometrial cancer of the uterine corpus. In some embodiments, the uterine cancer includes uterine sarcoma. In some embodiments, the uterine sarcoma includes uterine carcinosarcoma. In some embodiments, the BET inhibitor inhibits any one or more of the following bromodomains: BRD2, BRD3, and BRD4. In some embodiments, the BET inhibitor inhibits BRD4 and BRD2. In some embodiments, the BET inhibitor inhibits BRD3 and BRD4. In some embodiments, the BET inhibitor inhibits the BD1 bromodomain of BRD2, BRD3, BRD4, or any combination thereof. In some embodiments, the BET inhibitor inhibits the BD2 bromodomain of BRD2, BRD3, BRD4, or any combination thereof. In some embodiments, the BET inhibitor comprises a selective BET inhibitor. In some embodiments, the selective BET inhibitor inhibits any one or more of the following bromodomains: BRD2, BRD3, and BRD4. In some embodiments, the selective BET inhibitor is selective for BRD4 and BRD2. In some embodiments, the selective BET inhibitor is selective for BRD2, BRD3, and BRD4. In some embodiments, the selective BET inhibitor inhibits the BD1 bromodomain of BRD2, BRD3, BRD4, or any combination thereof. In some embodiments, the selective BET inhibitor includes GSK778. In some embodiments, the selective BET inhibitor inhibits the BD2 bromodomain of BRD2, BRD3, BRD4, or any combination thereof. In some embodiments, the selective BET inhibitor includes GSK046, ABBV-744, compound 9, or any combination thereof. In some embodiments, the loss of function or deletion is targeted at the EP300 gene.

[0011] In some embodiments, this document provides a method for treating cancer in a subject in need, the method comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a bromine domain and an additional terminal domain (BET) inhibitor; the cancer has been previously identified as involving loss or deletion of the EP300 gene; The BET inhibitors mentioned above include compounds of formula IV. Or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein: R1 is selected from hydrogen; deuterium; -C 1-6 Alkyl group; or -C3-8 carbon ring; and each of which, in each occurrence, is independently and optionally substituted by 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents, in each occurrence, is independently selected from deuterium, halogen, OH, -CN, -C 1-8 Alkyl, -C 1-8 Alkoxy, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 (alkyl)2 or -C3-8 carbon ring; R2 is selected from hydrogen; deuterium; halogen; -OR 21 ;-NR 21 R 22 -CN; -SR 21 ;-SOR 21 ;-SO2R 21 ;-SO2NR 21 R 22 ;-C 1-8 alkyl; Carboxyl group; -COOR 21 ;-CONR 21 R 22 ;-NR 21 COR 22 ;-NR 21 SO2R 22 ; or -C 3_8 The carbon ring; and each of the rings is independently and optionally substituted by 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, -OH, -CN, -NH2, -C each time it appears. 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 A carbon ring or a six-membered heterocycle containing one, two, or three heteroatoms selected from N or O; R 21 and R 22 Each of these terms is independently selected from hydrogen, deuterium, -OH, NH2, -CN, and -C each time it appears. 1-8 Alkyl; -C 1-8 Alkoxy group; -C 1-8 Alkylene-C 3-8 Carbon ring; or -C 3-8 Carbon ring; R 23 and R 24 Each of these elements is independently selected from hydrogen, deuterium, or -C each time it appears. 1-8 Alkyl; A is selected from or Y1 is selected from N or CRY1 Y2 is selected from O, S, and CR. Y1 R Y2 or NR Y2 ;R Y1 and R Y2 Each of these elements is independently selected from hydrogen, deuterium, halogen, -OH, NH2, -CN, -C1-6 alkyl, or -C each time it appears. 1-6 Alkoxy group; each of R3 and R4 is independently selected from hydrogen, deuterium, or -C each time it appears. 1-6 Alkyl groups; and each of them is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, -OH, -NH2, -CN, -C each time it appears. 1-6 Alkyl or -C 1-6 Alkyl group; n is selected from 0, 1, 2, 3, 4, 5 or 6; W1 is selected from hydrogen; deuterium; -F; -CI; -NH2; -CN; -OH; carboxyl group; -C 1-6 Alkyl; -C 1-6 Alkoxy group; -C 1-3 Alkylene-C 1-3 Alkoxy; phenyl; a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N or O; a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N or O; a 3-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 4-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 5-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 6-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 3-membered carbon ring; a 4-membered carbon ring; a 5-membered carbon ring; or a 6-membered carbon ring; and each of these is independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents each time it appears, and each of these substituents is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, -C 1-3 Alkyl, or -C 1-3 Alkyl group; W2 is selected from hydrogen; deuterium; -F; -CI; -NH2; -CN; -OH; carboxyl group; -C 1-3 Alkyl; -C 1-3Alkoxy; phenyl; naphthyl; 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 7-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 8-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 9-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 3-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; 4-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; A 5-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 6-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 3-membered carbon ring; a 4-membered carbon ring; a 5-membered carbon ring; or a 6-membered carbon ring; and each of these is independently and optionally substituted with 1, 2, 3, 4, or 5 substituents each time it appears, and each of these substituents is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy each time it appears; Z is selected from hydrogen, deuterium, halogen, -NH2, -CN, -OH, carboxyl, -C1.6 alkyl, or -C 1-6 Alkyl group.

[0012] In some embodiments, this document provides a method for treating cancer in a subject of need, the method comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a bromine domain and an additional terminal domain (BET) inhibitor; the cancer has been previously identified as containing a reduced amount or activity of p300 compared to wild-type p300; wherein the BET inhibitor comprises a compound of formula IV. Or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein: R1 is selected from hydrogen; deuterium; -C 1-6 Alkyl group; or -C3-8 carbon ring; and each of which, in each occurrence, is independently and optionally substituted by 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents, in each occurrence, is independently selected from deuterium, halogen, OH, -CN, -C 1-8 Alkyl, -C 1-8 Alkoxy, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 (alkyl)2 or -C3-8 carbon ring; R2 is selected from hydrogen; deuterium; halogen; -OR 21 ;-NR 21 R 22 -CN; -SR 21 ;-SOR 21 ;-SO2R 21 ;-SO2NR21 R 22 ;-C 1-8 alkyl; Carboxyl group; -COOR 21 ;-CONR 21 R 22 ;-NR 21 COR 22 ;-NR 21 SO2R 22 ; or -C 3_8 The carbon ring; and each of the rings is independently and optionally substituted by 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, -OH, -CN, -NH2, -C each time it appears. 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 A carbon ring or a six-membered heterocycle containing one, two, or three heteroatoms selected from N or O; R 21 and R 22 Each of these terms is independently selected from hydrogen, deuterium, -OH, NH2, -CN, -C1-8 alkyl, -C1-8 alkoxy, -C1-8 alkylene-C 3-8 Carbon ring; or -C 3-8 Carbon ring; R 23 and R 24 Each of these elements is independently selected from hydrogen, deuterium, or -C each time it appears. 1-8 Alkyl; A is selected from or Y1 is selected from N or CR Y1 Y2 is selected from O, S, and CR. Y1 R Y2 or NR Y2 ;R Y1 and R Y2 Each of these elements is independently selected from hydrogen, deuterium, halogen, -OH, NH2, -CN, -C1-6 alkyl, or -C each time it appears. 1-6 Alkoxy group; each of R3 and R4 is independently selected from hydrogen, deuterium, or -C each time it appears. 1-6 Alkyl groups; and each of them is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, -OH, -NH2, -CN, -C each time it appears. 1-6 Alkyl or -C 1-6 Alkyl group; n is selected from 0, 1, 2, 3, 4, 5 or 6; W1 is selected from hydrogen; deuterium; -F; -CI; -NH2; -CN; -OH; carboxyl group; -C 1-6 Alkyl; -C 1-6 Alkoxy group; -C 1-3Alkylene-C 1-3 Alkoxy; phenyl; a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N or O; a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N or O; a 3-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 4-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 5-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 6-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 3-membered carbon ring; a 4-membered carbon ring; a 5-membered carbon ring; or a 6-membered carbon ring; and each of these is independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents each time it appears, and each of these substituents is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, -C 1-3 Alkyl or -C 1-3 Alkyl group; W2 is selected from hydrogen; deuterium; -F; -CI; -NH2; -CN; -OH; carboxyl group; -C 1-3 Alkyl; -C 1-3 Alkoxy; phenyl; naphthyl; 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 7-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 8-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 9-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 3-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; 4-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; A 5-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 6-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 3-membered carbon ring; a 4-membered carbon ring; a 5-membered carbon ring; or a 6-membered carbon ring; and each of these is independently and optionally substituted with 1, 2, 3, 4, or 5 substituents each time it appears, and each of these substituents is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy each time it appears; Z is selected from hydrogen, deuterium, halogen, -NH2, -CN, -OH, carboxyl, -C1.6 alkyl, or -C 1-6 Alkyl group. In some embodiments, the loss of function is caused by a genetic mutation. In some embodiments, the BET inhibitor comprises compound 5: (Compound 5) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

[0013] In some embodiments, the BET inhibitor comprises compound 6: (Compound 6) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

[0014] In some embodiments, the BET inhibitor comprises compound 7: (Compound 7) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

[0015] In some embodiments, the BET inhibitor comprises compound 8: (Compound 8) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof. In some embodiments, the cancer includes bladder cancer, lung cancer, gynecological cancer, adrenocortical carcinoma, bone cancer, central nervous system (CNS) cancer, pancreatic cancer, gastrointestinal cancer, head and neck cancer, skin cancer, mesothelioma, schwannoma, lymphoma, renal cell carcinoma, salivary gland cancer, non-melanoma skin cancer, or combinations thereof. In some embodiments, the cancer includes lung cancer. In some embodiments, the lung cancer includes non-small cell lung cancer. In some embodiments, the non-small cell lung cancer includes squamous cell carcinoma, large cell carcinoma, adenocarcinoma, or combinations thereof. In some embodiments, the non-small cell lung cancer includes squamous cell carcinoma. In some embodiments, the non-small cell lung cancer includes large cell carcinoma. In some embodiments, the non-small cell lung cancer includes adenocarcinoma. In some embodiments, the lung cancer includes small cell lung cancer. In some embodiments, the cancer includes bladder cancer. In some embodiments, the bladder cancer includes carcinoma. In some embodiments, the carcinoma includes urothelial carcinoma. In some embodiments, the cancer includes pancreatic cancer. In some embodiments, the skin cancer includes melanoma. In some embodiments, the CNS cancer includes glioma. In some embodiments, the CNS cancer includes neuroepithelial tumors. In some embodiments, the lymphoma includes non-Hodgkin's lymphoma. In some embodiments, the lymphoma includes diffuse large B-cell lymphoma. In some embodiments, the lymphoma includes follicular lymphoma. In some embodiments, the lymphoma includes marginal zone lymphoma. In some embodiments, the lymphoma includes mature B-cell tumors. In some embodiments, the gastrointestinal cancer includes gastrointestinal stromal tumors, esophageal gastric cancer, gastrointestinal neuroendocrine tumors, small bowel cancer, anal cancer, colon cancer, or combinations thereof. In some embodiments, the gastrointestinal cancer includes gastrointestinal stromal tumors. In some embodiments, the gastrointestinal cancer includes esophageal gastric cancer. In some embodiments, the gastrointestinal cancer includes gastrointestinal neuroendocrine tumors. In some embodiments, the gastrointestinal cancer includes small bowel cancer. In some embodiments, the gastrointestinal cancer includes anal cancer. In some embodiments, the gastrointestinal cancer includes colon cancer. In some embodiments, the colon cancer includes colorectal cancer. In some embodiments, the gynecological cancer includes cervical cancer. In some embodiments, the gynecological cancer includes ovarian cancer. In some embodiments, the gynecological cancer includes sex cord-stromal tumors. In some embodiments, the gynecological cancer includes vaginal cancer. In some embodiments, the cancer includes uterine cancer. In some embodiments, the uterine cancer includes endometrial cancer or uterine sarcoma. In some embodiments, the uterine cancer includes endometrial cancer. In some embodiments, the endometrial cancer includes endometrial cancer of the uterine corpus. In some embodiments, the uterine cancer includes uterine sarcoma. In some embodiments, the uterine sarcoma includes uterine carcinosarcoma.In some embodiments, the subject has NUT midline carcinoma. In some embodiments, the subject has castration-resistant prostate cancer. In some embodiments, the subject has solid or liquid carcinoma. In some embodiments, the subject has liquid carcinoma selected from myelofibrosis. In some embodiments, the subject has liquid carcinoma selected from myeloma and leukemia. In some embodiments, the subject has liquid carcinoma selected from leukemia. In some embodiments, the leukemia is selected from acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). In some embodiments, the loss of function or deletion is targeted at the EP300 gene. In some embodiments, R1 is selected from hydrogen; deuterium; -C. 1-6 Alkyl group; or -C3-8 carbon ring; and each of which, in each occurrence, is independently and optionally substituted by 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents, in each occurrence, is independently selected from deuterium, halogen, OH, -CN, -C 1-8 Alkyl or -C 1-8 Alkoxy group; R2 is selected from hydrogen; deuterium; halogen; -C 1-8 alkyl; Carboxyl group; -COOR 21 ; or -CONR 21 R 22 Each of these elements is independently and optionally substituted by 1, 2, 3, 4, 5, or 6 substituents each time it appears, and each of these substituents is independently selected from deuterium, halogen, -OH, -CN, -NH2, and -C each time it appears. 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 A carbon ring, or a six-membered heterocycle containing one, two, or three heteroatoms selected from N or O; R 21 and R 22 Each of these terms is independently selected from hydrogen; deuterium; -OH; NH2; -CN; -C1-8 alkyl; or -C 3-8 Carbon ring; R 23 and R 24 Each of these elements is independently selected from hydrogen, deuterium, or -C each time it appears. 1-8 Alkyl; A is selected from or Y1 is selected from N or CR Y1 Y2 is selected from O, S, and CR. Y1 R Y2 or NR Y2 ;R Y1 and R Y2 Each of these elements is independently selected from hydrogen, deuterium, halogen, -OH, NH2, -CN, -C1-6 alkyl, or -C each time it appears. 1-6Alkoxy group; each of R3 and R4 is independently selected from hydrogen, deuterium, or -C each time it appears. 1-6 Alkyl groups; and each of them is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, -OH, -NH2, -CN, -C each time it appears. 1-6 Alkyl or -C 1-6 Alkyl group; n is selected from 0, 1 or 2; W1 is selected from hydrogen; deuterium; -F; -CI; -NH2; -CN; -OH; carboxyl group; -C 1-6 Alkyl; -C 1-6 Alkyl group; a 6-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N and O; wherein each heteroatom is independently and optionally substituted by 1, 2, 3, 4, 5, or 6 substituents each time it appears, and each of the substituents is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, -C 1-3 Alkyl or -C 1-3 Alkyl group; W2 is selected from hydrogen; deuterium; -F; -CI; -NH2; -CN; -OH; carboxyl group; -C 1-3 Alkyl; -C 1-3 Alkoxy; phenyl; naphthyl; a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; and each of these is independently and optionally substituted with 1, 2, 3, 4, or 5 substituents each time it appears, and each of these substituents is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy each time it appears; Z is selected from hydrogen, deuterium, halogen, -NH2, -CN, -OH, or -C 1-6Alkoxy. In some embodiments, the compound of formula IV is selected from: (S)-2-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; (S)-2-(6-(3,5-dimethylisoxazol-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 2-(6-(1,4-dimethyl-1H-1) 2,3-Triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-fluoropyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl- 4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 2-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-((tetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol Pyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-carboxamide;2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propyl-2-amine; 2-(4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)- 1-Methyl-6-(1-Methyl-4-(methyl-d3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-4-yl)(tetrahydro-2H-pyran) -4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-methoxypyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[ [3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; and 4-((6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methyl)morpholine.

[0016] Incorporation All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference. If any publication or patent or patent application incorporated by reference contradicts the disclosure contained in this specification, this specification is intended to supersede and / or give precedence to any such contradictory material. Attached Figure Description

[0017] The novel features of the invention are specifically set forth in the appended claims. A better understanding of the features and advantages of the invention will be obtained by referring to the following detailed description and accompanying drawings, which illustrate embodiments utilizing the principles of the invention, in which: Figure 1A The inhibitory activity of AZD-5153 in H2009 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0018] Figure 1B The inhibitory activity of AZD-5153 in SW780 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0019] Figure 2A The inhibitory activity of BI-2536 in SW780 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0020] Figure 2B The inhibitory activity of BI-2536 in KP4 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0021] Figure 3 The inhibitory activity of BI-894999 was demonstrated in KP4 cells with wild-type EP300 or EP300 knockout.

[0022] Figure 4A The inhibitory activity of BMS-986158 in SW780 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0023] Figure 4B The inhibitory activity of BMS-986158 in KP4 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0024] Figure 5A The inhibitory activity of GSK525762 in SW780 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0025] Figure 5B The inhibitory activity of GSK525762 in KP4 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0026] Figure 6 The inhibitory activity of INCB054329 in KP4 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0027] Figure 7A The inhibitory activity of OTX-015 in RT11284 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0028] Figure 7B The inhibitory activity of OTX-015 in KP4 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0029] Figure 7C The inhibitory activity of OTX-015 in SW780 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0030] Figure 7D The inhibitory activity of OTX-015 in Calu1 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0031] Figure 8A The inhibitory activity of PLX-51107 in RT11284 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0032] Figure 8B The inhibitory activity of PLX-51107 in Calu1 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0033] Figure 8C The inhibitory activity of PLX-51107 in KP4 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0034] Figure 9 The inhibitory activity of TEN-010 in KP4 cells with wild-type EP300 or EP300 knockout was demonstrated.

[0035] Figure 10 The figure illustrates the inhibitory activity of C177 (JQ1) in KP4 cells with wild-type EP300 or EP300 knockout. Figure 11 The in vivo activities of PLX-51107 and OTX-015 in a PDX model of bladder cancer with EP300 loss-of-function mutation are illustrated.

[0036] Figure 12 The figure illustrates the changes in body weight in mice with a bladder cancer PDX model containing an EP300 loss-of-function mutation after administration of PLX-51107 or OTX-015.

[0037] Figure 13 The inhibitory activity of AZD-5153 in H2009 cells with wild-type EP300 or EP300 knockout is illustrated.

[0038] Figure 14 The inhibitory activity of TEN-010 in KP4 cells with wild-type EP300 or EP300 knockout is illustrated.

[0039] Figure 15 The inhibitory activity of INCB057643 in KP4 cells with wild-type EP300 or EP300 knockout is illustrated.

[0040] Figure 16 The inhibitory activity of INCB057643 in SW780 cells with wild-type EP300 or EP300 knockout is illustrated.

[0041] Figure 17The inhibitory activity of INCB057643 in HCC827 cells with wild-type EP300 or EP300 knockout is illustrated.

[0042] Figure 18 The inhibitory activity of CC-90010 in KP4 cells with wild-type EP300 or EP300 knockout is illustrated.

[0043] Figure 19 The illustration shows the inhibitory activity of BI-2536 in KP4 cells with wild-type EP300 or EP300 knockout. BI-2536 is a potent Plk1 inhibitor with a Plk1 specificity of >40x for BRD4.

[0044] Figure 20 The inhibitory activity of PLX-51107 in KP4 cells with wild-type EP300 or EP300 knockout is illustrated.

[0045] Figure 21 The inhibitory activity of PLX-51107 in Calu1 cells with wild-type EP300 or EP300 knockout is illustrated.

[0046] Figure 22 The inhibitory activity of PLX-51107 in SW780 cells with wild-type EP300 or EP300 knockout is illustrated.

[0047] Figure 23 The inhibitory activity of arobuxue in Calu1 cells with wild-type EP300 or EP300 knockout is illustrated.

[0048] Figure 24 The inhibitory activity of arobuxue in KP4 cells with wild-type EP300 or EP300 knockout is illustrated.

[0049] Figure 25 The inhibitory activity of ODM-207 in KP4 cells with wild-type EP300 or EP300 knockout is illustrated.

[0050] Figure 26 The figure illustrates the inhibitory activity of GSK778 in KP4 cells with wild-type EP300 or EP300 knockout.

[0051] Figure 27 The figure illustrates the inhibitory activity of GSK778 in Calu1 cells with wild-type EP300 or EP300 knockout.

[0052] Figure 28 The figure illustrates the inhibitory activity of GSK046 in KP4 cells with wild-type EP300 or EP300 knockout.

[0053] Figure 29 The inhibitory activity of ABBV-744 in Calu1 cells with wild-type EP300 or EP300 knockout is illustrated.

[0054] Figure 30 The figure illustrates the inhibitory activity of ABBV-744 in KP4 cells with wild-type EP300 or EP300 knockout.

[0055] Figure 31 The figure illustrates the inhibitory activity of compound 5 in KP4 cells with wild-type EP300 or EP300 knockout.

[0056] Figure 32 The inhibitory activity of mivebuse in KP4 cells with wild-type EP300 or EP300 knockout is illustrated.

[0057] Figure 33 The inhibitory activity of ZEN-3694 in KP4 cells with wild-type EP300 or EP300 knockout is illustrated.

[0058] Figure 34 The figure illustrates the inhibitory activity of Trotabresib in KP4 cells with wild-type EP300 or EP300 knockout.

[0059] Figure 35 The figure illustrates the inhibitory activity of Molibresib in KP4 cells with wild-type EP300 or EP300 knockout.

[0060] Figure 36 The inhibitory activity of Molibresib in SW780 cells with wild-type EP300 or EP300 knockout is illustrated.

[0061] Figure 37 The inhibitory activity of pilarisin in Calu1 cells with wild-type EP300 or EP300 knockout is illustrated.

[0062] Figure 38 The inhibitory activity of pilarisin in KP4 cells with wild-type EP300 or EP300 knockout is illustrated.

[0063] Figure 39 The inhibitory activity of pilarisin in SW780 cells with wild-type EP300 or EP300 knockout is illustrated.

[0064] Figure 40 The inhibitory activity of pilarisin in SW1271 cells with wild-type EP300 or EP300 knockout is illustrated.

[0065] Figure 41The inhibitory activity of INCB054329 in KP4 cells with wild-type EP300 or EP300 knockout is illustrated.

[0066] Figure 42 The figure illustrates the inhibitory activity of BI-894999 in KP4 cells with wild-type EP300 or EP300 knockout.

[0067] Figure 43 The figure illustrates the inhibitory activity of Pelabresib in KP4 cells with wild-type EP300 or EP300 knockout.

[0068] Figure 44 The inhibitory activity of C177 (JQ1) in KP4 cells with wild-type EP300 or EP300 knockout is illustrated.

[0069] Figure 45A The illustration shows a volcano plot depicting the effect size and significance of driver gene changes in CRISPR knockout / bilarisell pharmacogenetic screening in KP4 cells.

[0070] Figure 45B The illustration shows a volcano plot depicting the effect size and significance of driver gene changes in CRISPR knockout / bilarisell pharmacogenetic screening in MDAMB231 triple-negative breast cancer cells.

[0071] Figure 46A The figure illustrates the change in tumor volume over time in the bladder cancer PDX model J000108112. The mouse model was treated with the medium, 20 mg / kg piracetam, or 20 mg / kg PLX-51107.

[0072] Figure 46B The figure illustrates the change in body weight over time in the bladder cancer PDX model J000108112. The mouse model was treated with the medium, 20 mg / kg piracetam, or 20 mg / kg PLX-51107.

[0073] Figure 46C The figure illustrates the change in tumor volume over time in the bladder cancer PDX model J000108112. The mouse model was treated with either the valerate or 20 mg / kg bilarex.

[0074] Figure 46D The figure illustrates the change in tumor volume over time in the bladder cancer PDX model J000108112. The mouse model was treated with either the medium or 20 mg / kg PLX-51107.

[0075] Figure 47AThe figure illustrates the change in tumor volume over time in the lung cancer PDX model TM00244. The mouse model was treated with the medium, 20 mg / kg piracetam, or 20 mg / kg PLX-51107.

[0076] Figure 47B The figure illustrates the change in body weight over time in the lung cancer PDX model TM00244. The mouse model was treated with the medium, 20 mg / kg piracetam, or 20 mg / kg PLX-51107.

[0077] Figure 47C The figure illustrates the change in tumor volume over time in the lung cancer PDX model TM00244. The mouse model was treated with either the drug or 20 mg / kg bilarex.

[0078] Figure 47D The figure illustrates the change in tumor volume over time in the lung cancer PDX model TM00244. The mouse model was treated with either the medium or 20 mg / kg PLX-51107. Detailed Implementation

[0079] While various embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Numerous variations, modifications, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.

[0080] This disclosure provides novel approaches to treating or preventing cancer, resulting in unexpectedly superior cancer cell suppression or cancer therapy. The methods presented herein can overcome the challenges associated with BET inhibitors by utilizing synthetic lethality.

[0081] Precision medicine can offer some of the latest cancer treatments. Targeted therapy can aim to leverage the biology of the disease and define which patients should receive specific treatments. One concept behind this approach is that the molecular characteristics of a patient's tumor can influence the clinical response to drugs and can therefore be used to guide therapy (e.g., drug selection). Thus, precision medicine can lead to improved efficacy (e.g., enhanced inhibition of tumor cell growth or increased tumor cell death) and reduced toxicity.

[0082] Tumor genetics can be central to this approach. For example, cancer may be caused by driver mutations that confer a selective advantage and may cause cancer cells to proliferate. Driver mutations can be used to define patients and can be highly predictive of drug activity; that is, the presence of a specific driver mutation can be an indicator of the effectiveness of a given therapy. Approximately one-third of cancers are likely caused by driver mutations that induce gain-of-function (GOF) mutations in oncogenes and produce protein products that can be therapeutically targeted. The remaining two-thirds of cancers are caused by loss-of-function (LOF) mutations in tumor suppressor genes (TSGs). In healthy cells, TSGs play a role in controlling cell growth and division; loss-of-function mutations in these genes can lead to uncontrolled growth and cancer. These types of cancers are generally more difficult to target than those caused by GOF mutations because in LOF-mutant cancers, the lack of a functional protein is what causes tumorigenesis. Therefore, targets are more difficult to identify. As evidence of this difference in therapeuticability, drugs exist for approximately two-thirds of oncogenes, but only for about 2% of tumor suppressor genes (e.g., PARPi targeting homologous recombination defects such as BRCA1 / 2, ATM, and ATR mutations). One potential approach to targeting LOF cancers is to exploit the vulnerability specific to tumor cells by identifying synthetic lethal (SL) interactions. In a synthetic lethal relationship between two genes, loss of function of either gene is tolerated, but loss of function of both genes is intolerable. Since only tumor cells contain driver mutations, drugs that specifically target these mutations will only affect these tumor cells, and off-target effects (such as toxicity) are expected to be minimal. This approach can be applied to identify genetic dependence and small molecule sensitivity in cancer cell lines. As evidence of the importance of this approach, large consortia are undertaking large-scale and ongoing efforts to comprehensively map synthetic lethal networks in hundreds of cancer cell lines, with the goal of identifying drug targets and patients expected to respond best to these drug targets.

[0083] While these efforts have provided valuable insights and identified potential drug candidates, significant challenges remain. For example, many patients do not benefit from targeted therapy because large-scale screening generates new target predictions and supplies the drug development pipeline at the starting point, thus treatment takes years, and drugs identified in screening (e.g., small molecule screening) may not reproduce the genetic perturbation profile, and SL relationships identified in cell lines may not migrate to the patient's tumor.

[0084] Many systematic approaches, such as cancer dependency mapping, have produced comprehensive maps of synthetic lethality in human cancer cells. Novel uses of drugs for genetically targeted cancer therapies can be predicted based on drug targets with synthetic lethality associated with mutations prevalent in cancer patients. However, this approach has limitations because pharmacological inhibition is difficult to reproduce genetic deletions of known drug targets. For more information, see: Goncalves E, et al. Drug mechanism-of-action discovery through the integration of pharmacological and CRISPR screens. Mol. Syst. Biol. 2020, 16, e9405 and Babak T, et al. Abstract 4035: Driver-gene dependencies reveal clinically actionable drug repositioning opportunities. Cancer Res (2022) 82 (12_Supplement): 4035.

[0085] The development of BET inhibitor resistance is receiving increasing attention because it can emerge early in the treatment of some cancers. The mechanisms leading to BET inhibitor resistance are multifactorial. Interestingly, none of the reported resistance mechanisms are related to genetic aberrations in the bromine domain (i.e., BRD2 / 3 / 4 mutations). In ovarian cancer, long-term BET inhibitor therapy has been reported to lead to receptor tyrosine kinase reprogramming, subsequently resulting in resistance to BET inhibitors. In colorectal cancer, activated interleukin-6 / 8-Janus kinase 2 signaling is known to promote Brd4 phosphorylation. Phosphorylated Brd4 becomes more stable and binds to BET inhibitors with lower affinity, thus contributing to BET inhibitor resistance. In AML and pancreatic cancer cells, compensatory upregulation of MYC via the WNT pathway has been reported to reduce cancer cell responsiveness to BET inhibitors. Furthermore, JQ1-resistant AML cells do not undergo apoptosis but instead shift to pro-survival autophagy. JQ-1-induced autophagy in drug-resistant AML cells is associated with upregulation of Beclin 1, increased LC3-II expression, and accumulation of autophagosomes, independent of mTOR signaling. In triple-negative breast cancer, resistance to BET inhibitors is mediated by a bromodomain-independent mechanism. In prostate cancer, loss-of-function mutations in SPOP (the E3 ubiquitin ligase of Brd4) have been shown to confer resistance to BET inhibitors by weakening ubiquitination-mediated Brd4 degradation. Maintenance of MYC expression has been reported to promote primary resistance to BET inhibitors in castration-resistant prostate cancer. Acquired resistance has been demonstrated after long-term treatment with BET-targeted PROTACs based on CRBN or VHL, due to genomic alterations that impair the core components of the CRBN or VHL E3 ligase complex. On the other hand, Brd4 hyperphosphorylation, caused by downregulation of PP2A phosphatase and an increased BCL2L1 / BCL-XL expression ratio, has been reported to contribute to BET inhibitor resistance in triple-negative breast cancer. In pancreatic cancer, long-term treatment with JQ-1 has been shown to trigger a rebound increase in BET inhibitor target genes, including FOSL1 and HMGA2. Exploring the synthetic lethal relationship with BET inhibitors could provide a solution to this problem.

[0086] Synthetic lethality is a phenomenon where the simultaneous loss of function or deletion (or a combination of both) of two genes leads to cell death, while the loss of function of either gene alone does not cause cell death. This concept can be used in cancer research as a target-based therapeutic strategy, where the goal is to identify gene pairs whose combined inhibition leads to cell death in cancer cells but not in non-cancer cells. A key concept behind synthetic lethality is targeting vulnerabilities in cancer cells that are absent in normal cells. Since cancer cells already possess mutated genes, a promising approach could be to identify and subsequently pharmacologically target the synthetic lethal partner of one of these mutated genes. However, identifying synthetic lethal gene pairs and further identifying pharmacological interventions to target the synthetic lethal partner remains a significant challenge.

[0087] In certain embodiments, this disclosure provides methods and kits for treating cancer with synthetic lethality. Synthetic lethality can occur in cancers including those with loss-of-function mutations or deletions of the EP300 gene, through the administration of a BET inhibitor. In some embodiments, the methods provided herein include determining the presence (e.g., in a subject) of a mutation or deletion of the EP300 gene. In some embodiments, the method includes treating a cancer that includes a loss-of-function mutation in the EP300 gene or a deletion of the EP300 gene or a portion thereof. In some embodiments, the loss-of-function mutation is in the EP300 gene. In some embodiments, the deletion is a deletion of the EP300 gene. In some embodiments, the BET inhibitor inhibits BRD2, BRD3, BRD4, or combinations thereof. In some embodiments, the BET inhibitor inhibits BD1 or BD2. In some embodiments, the BET inhibitor inhibits BD2. In some embodiments, the BET inhibitor is a selective BD2 inhibitor. In some embodiments, the selective BD2 inhibitor includes GSK046, ABBV-744, or compound 9. In some embodiments, the BET inhibitor is a selective BD1 inhibitor. In some implementations, selective BD1 inhibitors include GSK778.

[0088] I. Methods of treating cancer In some embodiments, this document provides a method for treating cancer in a subject of need, the method comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a bromine domain and an extra terminal domain (BET) inhibitor, and the cancer has been previously identified as involving loss of function or deletion of the EP300 gene. In some embodiments, the loss of function is caused by a genetic mutation. In some embodiments, the patient is not concurrently receiving (Compound 1) or (Compound 2). In some embodiments, the method includes the premise that the BET inhibitor does not inhibit CREB-binding protein (CREBBP). In some embodiments, the method includes the premise that the BET inhibitor does not inhibit Plk1. In some embodiments, the selectivity of the BET inhibitor to BET is at least 10x higher than that to Plk1. In some embodiments, the method includes the premise that the BET inhibitor is not JQ1. In some embodiments, the method includes the premise that the cancer is not triple-negative breast cancer. In some embodiments, the method includes the premise that the BET inhibitor is not JQ1 and the cancer is not triple-negative breast cancer.

[0089] In some embodiments, this document further provides a method of treating cancer in a subject of need, the method comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a bromine domain and an additional terminal domain (BET) inhibitor; the cancer has been previously identified as containing a reduced amount or activity of p300 compared to wild-type p300; and the patient has not received or has not previously received compound 1 or compound 2. In some embodiments, the cancer has been previously identified as containing a reduced amount of p300 compared to wild-type p300. In some embodiments, the cancer has been previously identified as containing a reduced activity of p300 compared to wild-type p300. In some embodiments, the method includes the premise that the BET inhibitor does not inhibit CREB-binding protein (CREBBP). In some embodiments, the method includes the premise that the BET inhibitor does not inhibit Plk1. In some embodiments, the method includes the premise that the BET inhibitor is not JQ1. In some embodiments, the method includes the premise that the cancer is not triple-negative breast cancer. In some embodiments, the method includes the premise that the BET inhibitor is not JQ1 and the cancer is not triple-negative breast cancer.

[0090] In some embodiments, the subject is not simultaneously receiving compound 1 or compound 2 and the BET inhibitor. In some embodiments, the subject has not previously received compound 1 or compound 2. In some embodiments, the BET inhibitors include ABBV-075, ABBV-744, apatadone, APL-581, ARV-825, AZD-5153, BI-6727, BI-894999, BMS-986158, BOS-475, BPI-23314, CD-161, CG-223, CK-103, CN-470, FT-1101, GNE-0011, GS-5829, GS-626510, GSK525762, I-BET151, INCB054329, INCB57643, JQ1LY-294002, NEO2734, ODM-207, OMT-001, OMT-002, OTX-015, Pelabresib, and PLX-2853. (OPN-2853), PLX-51107 (OPN-51107), TEN-010, RVX-297, SRX-2523, SRX-3225, SRX-3254, SW-064652, SYHA-1801, TTI-281, Zen-3694, CPI-0610, INCB0543294, JAB-8263, INCB057643, CC-90010, Arobresib, GSK778, GSK046, Mivibusib, Trobaresib, Molibresib, Pelabresib, or combinations thereof. In some embodiments, the BET inhibitor includes AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, INCB57643, OTX-015, PLX-51107, or combinations thereof. In some embodiments, the BET inhibitor includes compound 5. In some embodiments, the BET inhibitor includes compound 9. In some embodiments, the BET inhibitor includes AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, OTX-015, PLX-51107, INCB057643, TEN-010, CC-90010, arobuxe, ODM-207, GSK778, GSK046, ABBV-744, mivebuxe, trotabresib, molibresib, piracetam, pelabresib, or combinations thereof. In some embodiments, the BET inhibitor is a small molecule compound.

[0091] In some embodiments, the BET inhibitor comprises a compound of formula (I): Or its pharmaceutically acceptable salts, tautomers, stereoisomers, or deuterated analogs, wherein: R 1 X is a cyano, halogenated, or optionally substituted with one to three (C1-C3) alkyl groups independently selected from halogenated, methyl, ethyl, methoxy, and ethoxy groups; and when present, X is halogenated. In some embodiments, R 1 It is (C1-C2) alkyl, cyano, or fluorine. In some embodiments, R 1 It is methyl. In some embodiments, R 1 It is fluorine. In some implementations, R 1 It is a cyano group.

[0092] In some embodiments, the BET inhibitor comprises a compound of formula (II): Or its pharmaceutically acceptable salts, tautomers, stereoisomers, or deuterated analogs, wherein: R 1 It is an (C1-C3) alkyl group optionally substituted with 1 to 3 substituents independently selected from halogenated, methyl, ethyl, methoxy, and ethoxy groups. In some embodiments, R 1 It is a methyl group.

[0093] In some embodiments, the BET inhibitor comprises a compound of formula (III): Or a pharmaceutically acceptable salt thereof, wherein: X is halogenated when present.

[0094] In some embodiments, the BET inhibitor comprises a compound of formula IV: Its pharmaceutically acceptable salt or its stereoisomer, wherein, R1 is selected from hydrogen; deuterium; -C 1-6 Alkyl; or -C 3-8 The carbon ring; and each of the rings is independently and optionally substituted by 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, OH, -CN, -C each time it appears. 1-8 Alkyl, -C 1-8 Alkoxy, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2 or -C 3-8 Carbon rings; R2 is selected from hydrogen; deuterium; halogen; -OR21 ;-NR 21 R22; -CN; -SR 21 ;-SOR 21 ;-SO2R 21 ;-SO2N R 21 R 22 ;-C 1-8 alkyl; Carboxyl group; -COOR 21 ;-CONR 21 R 22 ;-NR 21 COR 22 ;-NR 21 SO2R 22 ; or -C 3_8 The carbon ring; and each of the rings is independently and optionally substituted by 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, -OH, -CN, -NH2, -C each time it appears. 1-8 Alkyl, -C 1-8 Alkoxy, -C 3-8 Carbon rings or six-membered heterocycles containing one, two, or three heteroatoms selected from N or O; R 21 and R 22 Each of these terms is independently selected from hydrogen, deuterium, -OH, NH2, -CN, and -C each time it appears. 1-8 Alkyl; -C 1-8 Alkoxy group; -C 1-8 Alkylene-C 3-8 Carbon ring; or -C 3-8 Carbon rings; R 23 and R 24 Each of these elements is independently selected from hydrogen, deuterium, or -C each time it appears. 1-8 alkyl; A is selected from or ; Y1 is selected from N or CR Y1 ; Y2 is selected from O, S, and CR. Y1 R Y2 or NR Y2 ; R Y1 and R Y2 Each of these elements is independently selected from hydrogen, deuterium, halogen, -OH, NH2, -CN, and -C each time it appears. 1_6 Alkyl or -C 1-6 Alkoxy; Each of R3 and R4 is independently selected from hydrogen, deuterium, or -C each time it appears.1-6 Alkyl groups; and each of them is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, -OH, -NH2, -CN, -C each time it appears. 1-6 Alkyl or -C 1-6 Alkoxy; n is selected from 0, 1, 2, 3, 4, 5, or 6; W1 is selected from hydrogen; deuterium; -F; -CI; -NH2; -CN; -OH; carboxyl group; -C 1-6 Alkyl; -C 1-6 Alkoxy group; -C 1-3 Alkylene-C 1-3 Alkoxy; phenyl; a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N or O; a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N or O; a 3-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 4-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 5-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 6-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 3-membered carbon ring; a 4-membered carbon ring; a 5-membered carbon ring; or a 6-membered carbon ring; and each of these is independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents each time it appears, and each of these substituents is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, -C 1-3 Alkyl or -C 1-3 Alkoxy; W2 is selected from hydrogen; deuterium; -F; -CI; -NH2; -CN; -OH; carboxyl group; -C 1-3 Alkyl; -C 1-3Alkoxy; phenyl; naphthyl; 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 7-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 8-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 9-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 3-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; A 4-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 5-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 6-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 3-membered carbon ring; a 4-membered carbon ring; a 5-membered carbon ring; or a 6-membered carbon ring; and each of these is independently and optionally substituted with 1, 2, 3, 4, or 5 substituents each time it appears, and each of these substituents is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy each time it appears; Z is selected from hydrogen, deuterium, halogen, -NH2, -CN, -OH, carboxyl, -C1.6 alkyl, or -C 1-6 Alkyl group.

[0095] In some embodiments, R1 is selected from hydrogen; deuterium; -C1-6 alkyl; or -C3-8 carbide ring; and each of these is independently and optionally substituted by 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of these substituents is independently selected from deuterium, halogen, OH, -CN, -C 1-8 Alkyl or -C 1-8 Alkoxy; R2 is selected from hydrogen; deuterium; halogen; -C 1-8 alkyl; Carboxyl group; -COOR 21 ; or -CONR 21 R 22 Each of these elements is independently and optionally substituted by 1, 2, 3, 4, 5, or 6 substituents each time it appears, and each of these substituents is independently selected from deuterium, halogen, -OH, -CN, -NH2, and -C each time it appears. 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 Carbon rings or six-membered heterocycles containing one, two, or three heteroatoms selected from N or O; R 21 and R 22 Each of these terms is independently selected from hydrogen; deuterium; -OH; NH2; -CN; -C1-8 alkyl; or -C 3-8Carbon rings; R 23 and R 24 Each of these elements is independently selected from hydrogen, deuterium, or -C each time it appears. 1-8 alkyl; A is selected from or ; Y1 is selected from N or CR Y1 ; Y2 is selected from O, S, and CR. Y1 R Y2 or NR Y2 ; R Y1 and R Y2 Each of these elements is independently selected from hydrogen, deuterium, halogen, -OH, NH2, -CN, and -C each time it appears. 1-6 Alkyl or -C 1-6 Alkoxy; Each of R3 and R4 is independently selected from hydrogen, deuterium, or -C each time it appears. 1-6 Alkyl groups; and each of them is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, -OH, -NH2, -CN, -C each time it appears. 1-6 Alkyl or -C 1-6 Alkoxy; n is selected from 0, 1, or 2; W1 is selected from hydrogen; deuterium; -F; -CI; -NH2; -CN; -OH; carboxyl group; -C 1-6 Alkyl; -C 1-6 Alkyl group; a 6-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N and O; wherein each heteroatom is independently and optionally substituted by 1, 2, 3, 4, 5, or 6 substituents each time it appears, and each of the substituents is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, -C 1-3 Alkyl or -C 1-3 Alkoxy; W2 is selected from hydrogen; deuterium; -F; -CI; -NH2; -CN; -OH; carboxyl group; -C 1-3 Alkyl; -C 1-3Alkoxy; phenyl; naphthyl; a 5-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; a 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; and each of these, in each occurrence, is independently and optionally substituted by 1, 2, 3, 4 or 5 substituents, and each of these substituents, in each occurrence, is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; Z is selected from hydrogen, deuterium, halogen, -NH2, -CN, -OH, or -C. 1-6 Alkyl group.

[0096] In some embodiments, R1 is selected from hydrogen; deuterium; or -C1-6 alkyl. In some embodiments, R1 is selected from hydrogen; in some embodiments, R1 is selected from deuterium. In some embodiments, R1 is selected from -C1-6 alkyl.

[0097] In some implementations, R2 is selected from hydrogen; deuterium; halogen; -C 1-8 alkyl; ; or -CONR 21 R 22 Each of these elements is independently and optionally substituted by 1, 2, 3, 4, 5, or 6 substituents each time it appears, and each of these substituents is independently selected from deuterium, halogen, -OH, -CN, -NH2, and -C each time it appears. 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 The carbon ring or a six-membered heterocycle containing one, two, or three heteroatoms selected from N or O. In some embodiments, R2 is selected from hydrogen; deuterium; halogen; -C. 1-8 Alkyl groups; and each of them is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, -OH, -CN, -NH2, -C each time it appears. 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 A carbon ring or a six-membered heterocycle containing one, two, or three heteroatoms selected from N or O. In some embodiments, R2 is selected from hydrogen; -C 1-8 Alkyl groups; and each of them is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, -OH, -CN, -NH2, -C each time it appears. 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 The carbon ring or a six-membered heterocycle containing one, two, or three heteroatoms selected from N or O; in some embodiments, R2 is selected from -C.1-8 Alkyl group; wherein each of the substituents is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents in each occurrence, and each of the substituents is independently selected from deuterium, halogen, -OH, -CN, -NH2, -C in each occurrence. 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 The carbon ring or a six-membered heterocycle containing one, two, or three heteroatoms selected from N and O. In some embodiments, R 21 and R 22 Each of these terms is independently selected from hydrogen, deuterium, -OH, NH2, or -C each time it appears. 3-8 Carbon ring. In some implementations, R 21 and R 22 Each of these is independently selected from hydrogen; or deuterium, each time it appears. In some implementations, R 21 and R 22 Selected from hydrogen.

[0098] In some implementation schemes, R 23 and R 24 Each of these is independently selected from hydrogen or -C each time it appears. 1-8 Alkyl group. In some embodiments, R 23 and R 24 Each of the terms is selected independently from -C each time it appears. 1-2 alkyl.

[0099] In some implementation schemes, A is selected from or In some implementations, A is selected from... In some implementations, A is selected from... In some implementations, Y1 is selected from N or CR. Y1 In some implementations, Y1 is selected from N. In some implementations, Y1 is selected from CR. Y1 In some implementations, Y2 is selected from O, S, and CR. Y1 R Y2 or NR Y2 In some implementations, Y2 is selected from O. In some implementations, Y2 is selected from S. In some implementations, R... Y1 and R Y2 Each of them is independently selected from hydrogen, deuterium, or -C1-6 alkyl each time it appears.

[0100] In some implementations, each of R3 and R4 is independently selected from hydrogen, deuterium, or -C each time it appears. 1-6Alkyl groups; and each of them is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, or -C each time it appears. 1-6 Alkyl group. In some embodiments, each of R3 and R4 is independently selected from -C each time it appears. 1-6 Alkyl groups; and each of them is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium each time it appears.

[0101] In some implementations, n is selected from 1 or 2. In some implementations, n is selected from 1. In some implementations, n is selected from 2.

[0102] In some embodiments, W1 is selected from hydrogen; deuterium; -F; -Cl; -NH2; -CN; -OH; carboxyl; -C 1-6 Alkyl; -C 1-6 An alkoxy group; a six-membered heterocycle containing one, two, or three heteroatoms selected from N and O; wherein each heteroatom is optionally and independently substituted with one, two, three, four, five, or six substituents each time it appears, and each of the substituents is selected from deuterium, halogen, -NH2, -CN, or -OH each time it appears. In some embodiments, W1 is selected from -C. 1-6 Alkyl group; a six-membered heterocycle containing one or two heteroatoms selected from O; and each of which, in each occurrence, is optionally substituted independently by one, two, three, four, five, or six substituents, and each of said substituents, in each occurrence, is selected from deuterium, halogen, or -OH. In some embodiments, W1 is selected from -C. 1-6 Alkyl group; a 6-membered heterocycle containing one heteroatom selected from O; and each of the members is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is selected from halogens each time it appears.

[0103] In some embodiments, W2 is selected from hydrogen; deuterium; -F; -Cl; -NH2; -CN; -OH; carboxyl; -C 1-3 Alkyl; -C 1-3The alkyl group; phenyl group; a 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, or S; and each of these groups is independently and optionally substituted with 1, 2, 3, 4, or 5 substituents each time it appears, and each of these substituents is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy each time it appears. In some embodiments, W2 is selected from phenyl; a 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N; and each of these groups is independently and optionally substituted with 1, 2, 3, 4, or 5 substituents each time it appears, and each of these substituents is selected from deuterium, halogen, methyl, or methoxy each time it appears. In some embodiments, W2 is selected from phenyl; it is independently and optionally substituted with 1, 2, 3, 4, or 5 substituents each time it appears, and each of the substituents is selected from deuterium, halogen, methyl, or methoxy each time it appears. In some embodiments, W2 is selected from a 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N; it is independently and optionally substituted with 1, 2, 3, 4, or 5 substituents each time it appears, and each of the substituents is selected from deuterium, halogen, methyl, or methoxy each time it appears.

[0104] In some embodiments, Z is selected from hydrogen, deuterium, or halogen. In some embodiments, Z is selected from hydrogen or halogen. In some embodiments, Z is selected from hydrogen.

[0105] In some embodiments, the BET inhibitor comprises compound 5: (Compound 5) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

[0106] In some embodiments, the BET inhibitor comprises compound 6: (Compound 6) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

[0107] In some embodiments, the BET inhibitor comprises compound 7: (Compound 7) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

[0108] In some embodiments, the BET inhibitor comprises compound 8: (Compound 8) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

[0109] In some implementations, the BET inhibitor is selected from: (S)-2-(6-(3,5-dimethylisoxazo-4-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; (S)-2-(6-(3,5-dimethylisoxazo-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-fluoropyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 2-(6-(3,5-dimethylisoxazo-4-yl)-1-methyl-4-((tetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide; 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propyl-2-amine; 2-(4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-6-(1-methyl-4-(methyl-d3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-methoxypyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; and 4-((6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methyl)morpholine.

[0110] In some embodiments, the BET inhibitor comprises (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol.

[0111] In some embodiments, the BET inhibitor comprises a compound having the formula (Va): Or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analogue thereof, wherein: R 2 It is H; R 4 It is H; R 6 It is H; R 7 It is H, -OH, C 1-6 Alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; R 1 It is optional to be 1-3 R j heteroaryl groups with substituent groups; Each R j Independently selected from halogens, -CN, -OH, -NH2, -NO2, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -CH=C(R k (R) k -OR k -SR k -OC(O)R k -OC(S)R k -P(=O)HR k -P(=O)R k R k -PH(=O)OR k -P(=O)(OR) k )2、-OP(=O)(OR k )2、-C(O)H、-O(CO)OR k -C(O)R k -C(S)R k -C(O)OR k -C(S)OR k -S(O)R k -S(O)2R k -C(O)NHR k -C(S)NHR k -C(O)NR k R k -C(S)NR k R k -S(O)2NHR k -S(O)2NR k R k -C(NH)N HR k -C(NH)NR k R k -NHC(O)R k-NHC(S)R k -NR k C(O)R k -NR k C(S)R k -NHS(O)2R k -NR k S(O)2R k -NHC(O)NHR k -NHC(S)NHR k -NR k C(O)NH2、-NR k C(S)NH2、-NR k C(O)NHR k -NR k C(S)NHR k -NHC(O)NR k R k -NHC(S)NR k R k -NR k C(O)NR k R k -NR k C(S)NR k R k -NHS(O)2NHR k -NR k S(O)2NH2、-NR k S(O)2NHR k -NHS(O)2NR k R k -NR k S(O)2NR k R k -NHR k or -NR k R k ; Each R k H and C independently 1-6 Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, or cycloalkylalkyl; or When bonded to the same carbon or nitrogen atom, two R k The groups together form a 3 to 6-membered carbon ring or a 3 to 8-membered heterocycle having 1 to 2 heteroatoms selected from O, N or S as ring members, wherein the nitrogen or sulfur ring atom is optionally oxidized; R 3 It is H, halogen, -CN, or optionally substituted C. 1-6 Alkyl groups, optionally substituted deuterated C 1-6Alkyl, optionally substituted aryl, optionally substituted aryl-C 1-4 Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-C 1-4 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 cycloalkyl-C 1-4 Alkyl, optionally substituted heterocyclic alkyl, or optionally substituted heterocyclic alkyl-C 1-4 Alkyl; and R 5 It is optionally selected by one or two independent factors chosen from D, halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 R of halogenated alkoxy or -CN 11 Group substitution ; The wavy line indicates the connection point with the rest of the molecule.

[0112] In some embodiments, the BET inhibitor comprises a compound having formula (VI): Or its pharmaceutically acceptable salts, tautomers, stereoisomers, or deuterated analogs, wherein: R 1 X is a cyano, halogenated, or optionally substituted with one to three independent substituents selected from halogenated, methyl, ethyl, methoxy, and ethoxy (C1-C3) alkyl groups; when present, X is halogenated; R 2 It is an H, (C1-C3)alkyl, aryl, heteroaryl, or a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N or O; or a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N or O. In some embodiments, R 1 It is (C1-C2) alkyl, cyano, or fluorine. In some embodiments, R 1 It is methyl. In some embodiments, R 1 It is fluorine. In some implementations, R 1 It is cyano. In some implementations, R 2 It is H. In some implementations, R 2 It is a 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, the BET inhibitor comprises compound 3: (Compound 3), or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

[0113] In some embodiments, the BET inhibitor comprises compound 4: (Compound 4) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

[0114] In some embodiments, the BET inhibitor comprises a compound having formula (VII): Or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analogue thereof, wherein R is N, O, or S.

[0115] In some embodiments, the BET inhibitor comprises compound 9: (Compound 9) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

[0116] In some embodiments, the BET inhibitor includes ABBV-744: (ABBV-744) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

[0117] In some implementations, the cancers include bladder cancer, lung cancer, gynecological cancer, adrenocortical carcinoma, bone cancer, central nervous system (CNS) cancer, pancreatic cancer, gastrointestinal cancer, head and neck cancer, skin cancer, mesothelioma, schwannoma, lymphoma, renal cell carcinoma, salivary gland cancer, non-melanoma skin cancer, or combinations thereof.

[0118] In some embodiments, the cancer includes lung cancer. In some embodiments, the lung cancer includes non-small cell lung cancer. In some embodiments, the non-small cell lung cancer includes squamous cell carcinoma, large cell carcinoma, adenocarcinoma, or a combination thereof. In some embodiments, the non-small cell lung cancer includes squamous cell carcinoma. In some embodiments, the non-small cell lung cancer includes large cell carcinoma. In some embodiments, the non-small cell lung cancer includes adenocarcinoma. In some embodiments, the lung cancer includes small cell lung cancer. In some embodiments, the cancer includes breast cancer. In some embodiments, the breast cancer includes triple-negative breast cancer. In some embodiments, the BET inhibitor includes AZD-5153, INCB57643, OTX-015, PLX-51107, or a combination thereof. In some embodiments, the BET inhibitor includes AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, OTX-015, PLX-51107, INCB057643, TEN-010, CC-90010, arobuxe, ODM-207, GSK778, GSK046, ABBV-744, mivebuxe, trotabresib, molibresib, pilarresib, pelabresib, or combinations thereof.

[0119] In some embodiments, the cancer includes squamous cell carcinoma. In some embodiments, the cancer includes bladder cancer. In some embodiments, the bladder cancer includes carcinoma. In some embodiments, the cancer includes squamous cell carcinoma. In some embodiments, the carcinoma includes urothelial carcinoma. In some embodiments, the BET inhibitor includes AZD-5153, BMS-986158, GSK525762, INCB57643, OTX-015, PLX-51107, or combinations thereof. In some embodiments, the BET inhibitor includes AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, OTX-015, PLX-51107, INCB057643, TEN-010, CC-90010, arobuxare, ODM-207, GSK778, GSK046, ABBV-744, mivebuxe, trotabresib, molibresib, piracetam, pelabresib, or combinations thereof. In some embodiments, the cancer includes pancreatic cancer. In some embodiments, the BET inhibitor includes BI-894999, BMS-986158, GSK525762, INCB054329, INCB57643, OTX-015, PLX-51107, or combinations thereof. In some embodiments, the BET inhibitor includes AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, OTX-015, PLX-51107, INCB057643, TEN-010, CC-90010, arobuxe, ODM-207, GSK778, GSK046, ABBV-744, mivebuxe, trotabresib, molibresib, pilarresib, pelabresib, or combinations thereof.

[0120] In some embodiments, the skin cancer includes melanoma. In some embodiments, the CNS cancer includes glioma. In some embodiments, the CNS cancer includes neuroepithelial tumors. In some embodiments, the lymphoma includes non-Hodgkin's lymphoma. In some embodiments, the lymphoma includes diffuse large B-cell lymphoma. In some embodiments, the lymphoma includes follicular lymphoma. In some embodiments, the lymphoma includes marginal zone lymphoma. In some embodiments, the lymphoma includes mature B-cell tumors. In some embodiments, the gastrointestinal cancer includes gastrointestinal stromal tumors, esophageal cancer, gastrointestinal neuroendocrine tumors, small bowel cancer, anal cancer, colon cancer, or combinations thereof.

[0121] In some embodiments, the gastrointestinal cancer includes gastrointestinal stromal tumors. In some embodiments, the gastrointestinal cancer includes esophageal gastric cancer. In some embodiments, the gastrointestinal cancer includes gastroenterogenic neuroendocrine tumors. In some embodiments, the gastrointestinal cancer includes small bowel cancer. In some embodiments, the gastrointestinal cancer includes anal cancer. In some embodiments, the gastrointestinal cancer includes colon cancer. In some embodiments, the colon cancer includes colorectal cancer.

[0122] In some embodiments, the gynecological cancer includes cervical cancer. In some embodiments, the gynecological cancer includes ovarian cancer. In some embodiments, the gynecological cancer includes sex cord-stromal tumors. In some embodiments, the gynecological cancer includes vaginal cancer. In some embodiments, the cancer includes uterine cancer. In some embodiments, the uterine cancer includes endometrial cancer or uterine sarcoma. In some embodiments, the uterine cancer includes endometrial cancer. In some embodiments, the uterine cancer includes uterine sarcoma. In some embodiments, the endometrial cancer includes uterine corpus endometrial cancer. In some embodiments, the uterine sarcoma includes uterine carcinosarcoma. In some embodiments, the BET inhibitor inhibits any one or more of the following bromodomains: BRD2, BRD3, and BRD4. In some embodiments, the BET inhibitor inhibits BRD3 and BRD4. In some embodiments, the BET inhibitor inhibits BRD4 and BRD2. In some embodiments, the BET inhibitor inhibits the BD1 or BD2 bromodomain of BRD2, BRD3, and BRD4. In some embodiments, the BET inhibitor includes a selective BET inhibitor. In some embodiments, the selective BET inhibitor inhibits any one or more of the following bromodomains: BRD2, BRD3, and BRD4. In some embodiments, the selective BET inhibitor is selective for BRD4 and BRD2. In some embodiments, the selective BET inhibitor is selective for BRD2, BRD3, and BRD4. In some embodiments, the selective BET inhibitor selectively inhibits BD1. In some embodiments, the selective BET inhibitor selectively inhibits BD2. In some embodiments, the selective BD2 inhibitor includes GSK046, ABBV-744, or compound 9. In some embodiments, the selective BD1 inhibitor includes GSK778. In some embodiments, the selective BET inhibitor inhibits the BD1 or BD2 bromodomain of BRD2, BRD3, and BRD4. In some embodiments, the loss of function or deletion is targeted at the EP300 gene.

[0123] In some embodiments, the BET inhibitor comprises JAB-8263. In some embodiments, the BET inhibitor comprises a compound of formula IV. In some embodiments, the BET inhibitor comprises compound 5. In some embodiments, the BET inhibitor comprises compound 9.

[0124] In some embodiments, the cancer includes midline NUT carcinoma. In some embodiments, the cancer includes castration-resistant prostate cancer. In some embodiments, the cancer includes solid or liquid-filled carcinoma. In some embodiments, the liquid-filled carcinoma is selected from myelofibrosis. In some embodiments, the liquid-filled carcinoma is selected from myeloma and leukemia. In some embodiments, the liquid-filled carcinoma is selected from myeloma. In some embodiments, the liquid-filled carcinoma is selected from leukemia. In some embodiments, the leukemia is selected from acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). In some embodiments, the leukemia is selected from acute myeloid leukemia (AML). In some embodiments, the leukemia is selected from acute lymphoblastic leukemia (ALL).

[0125] a. BET inhibitors BET proteins can possess two N-terminal bromodomains (e.g., BD1 and BD2), a common structural feature with other BRD proteins, allowing them to interact with acetylated lysine residues on histones. BET proteins can structurally differ from other bromodomain-containing proteins because they contain an additional C-terminal (ET) domain. This ET domain can interact with a variety of cellular proteins, such as histone lysine N-methyltransferase (NSD3) and Jumonji domain-containing protein 6 (JMJD6), whose interactions are associated with acute myeloid leukemia (AML) and various solid tumors, respectively. The combination of dual BRDs and the protein-interacting ET domain allows BET proteins to efficiently mediate bimodal tethering of these cancer-associated factors to specific regions of chromatin.

[0126] BET proteins have four conserved mammalian members, including BRD-containing protein 2 (BRD2), BRD3, BRD4, and Brdt. Brdt is primarily expressed in germ cells, while BRD2, BRD3, and BRD4 are universally expressed in various tissues. All BET proteins employ a left-handed quadruple helical bundle structure (αZ, αA, αB, and αC), known as the "BRD fold." The αZ-αA (ZA) and αB-αC (BC) loops between the helices form a hydrophobic pocket that recognizes acetylated lysine residues. Sequence variations in the ZA and BC loops of different BRD folds in different BET proteins result in their distinct protein binding sites and affinities. Rapid induction of a selected target gene may require multiple BET proteins. Therefore, different BET proteins can have non-overlapping functions, and they can form protein complexes to elicit their biological activity.

[0127] BET proteins can act as transcriptional regulators. For example, BRD4 recruits PTEF-b (positive transcription elongation factor, a multi-protein complex crucial for transcriptional regulation) to the active transcription sites of cell growth-promoting genes such as MYC and NUT. During transcriptional elongation, BRD4 guides the correct nuclear localization and activation of PTEF-b to phosphorylate RNA polymerase II. Therefore, BRD4 can play a key role in promoting the enhancement of basal transcription to active elongation by RNA polymerase II. Simultaneously, the ET domain of BRD4 is known to recruit other transcriptional activators, including NSD3, JMJD6, and CHD4, to further promote gene transcription. On the other hand, BRD3 specifically binds to the GATA1 transcription factor and upregulates the expression of GATA1-dependent genes. BRD2 is known to interact with E2F, histone acetyltransferases, and histone deacetylases, recruiting them to gene promoters to couple histone acetylation to transcription in a PTEF-b-independent manner.

[0128] The BET protein family (e.g., BRD2, BRD3, and BRD4) has significant clinical implications due to its roles in cell cycle regulation, epigenetic sensing, and a range of cancers from oral, breast, prostate, lung, and colon cancer to myeloid leukemia. BET proteins contain a dibromodomain, a domain found in many cellular proteins that selectively binds acetylated histone markers. These include histone lysine N-methyltransferase protein ASH1L, histone acetyltransferase p300 (EP300), P300 / CBP-associated factor (PCAF), and the extended BET family. Current treatments rely on small-molecule acetylated mimics that block the ability of the bromodomain to bind its specific chromatin markers. Cancer inhibitors targeting the bromodomain are clinically limited because they target any protein containing the bromodomain, resulting in dose-limiting toxicity. There has been considerable interest in developing novel BET inhibitors for cancer treatment. Many new candidates are currently making progress through early clinical trials (Targeting BET bromodomains in cancer: Patric Trojer, Annual Review of Cancer Biology, 2022, Vol. 6: 313-336; Achieving clinical success with BET inhibitors as anti-cancer agents: Shortova, British Journal of Cancer, Vol. 124, pp. 1478-1490 (2021)).

[0129] In some embodiments, the BET inhibitors include ABBV-075, ABBV-744, apatadone, APL-581, ARV-825, AZD-5153, BI-6727, BI-894999, BMS-986158, BOS-475, BPI-23314, CD-161, CG-223, CK-103, CN-470, FT-1101, GNE-0011, GS-5829, GS-626510, GSK525762, I-BET151, INCB054329, INCB57643, JQ1LY-294002, NEO2734, ODM-207, OMT-001, OMT-002, OTX-015, Pelabresib, and PLX-2853. (OPN-2853), PLX-51107 (OPN-51107), TEN-010, RVX-297, SRX-2523, SRX-3225, SRX-3254, SW-064652, SYHA-1801, TTI-281, Zen-3694, CPI-0610, INCB0543294, INCB057643, CC-90010, Arobresib, GSK778, GSK046, Mivibusib, Trobaresib, Molibresib, Pelabresib, or combinations thereof. In some embodiments, the BET inhibitor includes AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, INCB57643, OTX-015, PLX-51107, JAB-8263, or combinations thereof. In some embodiments, the BET inhibitor includes AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, OTX-015, PLX-51107, INCB057643, TEN-010, CC-90010, arobuxare, ODM-207, GSK778, GSK046, ABBV-744, mivebuxil, trotabresib, molibresib, pilarresib, pelabresib, or combinations thereof. In some embodiments, the BET inhibitor comprises AZD-5153. In some embodiments, the BET inhibitor comprises BI-894999. In some embodiments, the BET inhibitor comprises BMS-986158. In some embodiments, the BET inhibitor comprises GSK525762. In some embodiments, the BET inhibitor comprises INCB054329. In some embodiments, the BET inhibitor comprises TEN-010.In some embodiments, the BET inhibitor comprises PLX-51107. In some embodiments, the BET inhibitor comprises PLX-2853. In some embodiments, the BET inhibitor comprises OTX-015. In some embodiments, the BET inhibitor comprises JAB-8263. In some embodiments, the BET inhibitor comprises INCB057643. In some embodiments, the BET inhibitor comprises CC-90010. In some embodiments, the BET inhibitor comprises arobuxe. In some embodiments, the BET inhibitor comprises ODM-207. In some embodiments, the BET inhibitor comprises GSK778. In some embodiments, the BET inhibitor comprises GSK046. In some embodiments, the BET inhibitor comprises ABBV-744. In some embodiments, the BET inhibitor comprises mirbuxe. In some embodiments, the BET inhibitor comprises Trobaresib. In some embodiments, the BET inhibitor comprises Molibresib. In some embodiments, the BET inhibitor comprises piracetam. In some embodiments, the BET inhibitor comprises Pelabresib. In some embodiments, the BET inhibitor comprises a compound of formula IV. In some embodiments, the BET inhibitor comprises compound 5. In some embodiments, the BET inhibitor comprises compound 9. The following provides a non-limiting description of some exemplary BET inhibitors.

[0130] i. JQ1 JQ1 (thieno-triazolo-1,4-diazazonium) is a BET inhibitor designed to mimic acetylated lysine. It has been shown to bind competitively and specifically with high affinity to the BD1 and BD2 bromodomains, thereby forming hydrogen bonds with conserved asparagine residues at the binding pocket. Using chromatin immunoprecipitation and fluorescence recovery assays after photobleaching, JQ1 has been shown to disengage BRD4 from chromatin and subsequently modulate genes regulated by the bromodomain. JQ1 exhibits potent antiproliferative activity in BRD4-dependent cancer cell lines and against NMC. However, due to its short half-life and rapid metabolism, JQ1 has not shown good therapeutic efficacy. ii. Bilarisse Pirarate, also known as OTX-015, is a potent bromodomain inhibitor of BRD2, BRD3, and BRD4, and has demonstrated an IC50 ranging from 92 to 112 nM. Pirarate (500 nM) showed significant reductions in BRD2, BRD4, and c-MYC, as well as increases in HEXIM1 protein. Treatment with 0.1, 1, and 5 μM piracerate induced the growth of the full-length HIV-1 transcript and virus in resting CD4+ T cells of infected individuals receiving repressive antiretroviral therapy (ART), while exhibiting minimal toxicity and effects on T cell activation. Pirarate-mediated HIV-1 activation involves increased CDK9 occupancy and phosphorylation of the RNAP II C-terminal domain (CTD). iii. PLX-51107 PLX-51107, commonly referred to as OPN-51107, has been shown to be a potent BET inhibitor with Kd values ​​of 1.6, 2.1, 1.7, and 5 nM for BD1 of BRD2, BRD3, BRD4, and BRDT, respectively, and Kd values ​​of 5.9, 6.2, 6.1, and 120 nM for BD2 of the same groups. PLX-51107 also interacts with the bromodomains of CBP and EP300 (Kd, in the 100 nM range). PLX-51107 (0.156–10 μM) inhibits CpG-induced proliferation. PLX-51107 can also lead to the accumulation of p21 and IκBα, reduce c-MYC levels, and regulate pro-apoptotic and anti-apoptotic proteins. PLX-51107 selectively regulates CLL driver genes and can interact with BRD2, BRD3, and BRD4. iv. PLX-2853 PLX-2853 is an orally administered, non-benzodiazepine bromide-domain and extra-terminal domain (BET) inhibitor exhibiting low nanomolar potency and a weak preference for binding to the second of the dibromo domains in BET proteins. By modulating genes crucial for leukemia cell proliferation and survival (e.g., BCL2 and MYC), PLX-2853 has demonstrated broad antileukemic activity in preclinical models as a single agent and in combination with other agents. Pharmacokinetic (PK) profiles in solid tumor patients show high peak plasma concentrations, a short terminal half-life (T<1 / 2 < 3 hours), and near-complete elimination from plasma within 9 hours of administration. This PK profile is hypothesized to allow for a brief target transition following daily dosing, followed by a recovery time, thereby improving tolerability. More information on BET inhibitors can be found in: U.S. Patent No. 9,771,363, published March 23, 2027, entitled “Heterocyclic compounds and uses thereof,” the entirety of which is incorporated herein by reference.

[0131] v. JAB-8263 JAB-8263 is a potent BET inhibitor with sub-nanomolar binding affinity. Preclinical studies have shown that JAB-8263 can effectively inhibit tumor growth, including hematologic malignancies and solid tumors, at very low concentrations. It is currently undergoing a multicenter, open-label Phase I / IIa clinical trial in China and the United States. More information on BET inhibitors such as JAB-8263 can be found in: US Patent No. 11,466,005, published October 11, 2022; and US 2021 / 0179617 A1, published June 17, 2021, both entitled "Tricyclic Compounds," and both are incorporated herein by reference.

[0132] b. The role of the EP300 gene in cancer The EP300 gene, also known as E1A binding protein P300, is a gene that encodes proteins involved in various cellular processes, including gene regulation, DNA repair, cell growth, and development.

[0133] The protein encoded by the EP300 gene is a histone acetyltransferase, meaning it can modify the structure of chromatin (a complex of DNA and protein in the cell nucleus) by adding acetyl groups to histone proteins. This modification is crucial for regulating gene expression because it makes DNA more accessible to transcription factors and other cellular machines involved in gene transcription.

[0134] In addition to its roles in histone acetylation and gene regulation, p300 proteins interact with a variety of other proteins, thereby participating in various intracellular signaling pathways and molecular interactions. It plays a crucial role in embryonic development, cell differentiation, and responses to environmental signals.

[0135] Mutations or dysregulation of the EP300 gene are associated with a variety of diseases and conditions, including certain cancers (such as colorectal cancers and hematologic malignancies), developmental disorders, and neurological conditions.

[0136] The EP300 protein plays a crucial role in regulating cell proliferation and differentiation; therefore, loss-of-function mutations or deletions in the EP300 gene may lead to cancer, or may exacerbate cancer severity or metastasis. Cancers containing mutated or deleted EP300 are believed to be present in more than 4% of all cancers; however, evidence suggests that loss-of-function EP300 is particularly common in bladder, lung, and pancreatic cancer (Table 1). Furthermore, studies have shown that tumors with EP300 mutations are associated with pathological T stage and lymph node metastasis, and lead to shorter predicted cumulative survival. Therefore, there is a need to provide treatment for individuals with cancers containing EP300 mutations or deletions.

[0137] The method described in this article can be used to treat cancers including those with loss-of-function mutations in the EP300 gene or deletions of the EP300 gene.

[0138] In some embodiments, cancers including EP300 loss-of-function mutations or EP300 deletions include breast cancer, urothelial carcinoma, rectal cancer, thymic carcinoma, sarcoma, or combinations thereof. In some embodiments, cancers include bladder cancer, rectal cancer, breast cancer, sarcoma, thymic carcinoma, or combinations thereof. In some embodiments, cancers include bladder cancer. In some embodiments, cancers include rectal cancer. In some embodiments, cancers include breast cancer. In some embodiments, cancers include sarcoma. In some embodiments, cancers include thymic carcinoma.

[0139] In some embodiments, the cancer includes urothelial carcinoma. In some embodiments, urothelial carcinoma includes bladder cancer. In some embodiments, the cancer includes rectal cancer. In some embodiments, the cancer includes thymic carcinoma. In some embodiments, the cancer includes sarcoma.

[0140] c. Identification of gene mutations or deletions (e.g., EP300 gene) In some embodiments, the cancer has been identified (e.g., previously identified) as including mutations or deletions (e.g., mutations or deletions in the EP300 gene). In some embodiments, the methods provided herein include determining the presence of a mutation or deletion in the EP300 gene (e.g., in a subject). The presence of a gene mutation or deletion can be determined before the composition is administered. For example, the determination of a mutation or deletion (e.g., a previous identification) can be performed months, weeks, days, hours, or even minutes before the composition is administered (e.g., a composition containing a BET inhibitor). The determination of the presence of a gene mutation (e.g., a loss-of-function mutation) or a gene deletion (e.g., the EP300 gene) can be performed in any suitable manner, including but not limited to identifying a gene mutation or deletion by any or more of the tests discussed herein.

[0141] In some implementations, mutations or deletions in the EP300 gene are a cause or consequence of cancer. In some implementations, mutations or deletions in the EP300 gene are not the result of pharmacological inhibition. For example, in such an implementation, the mutation or deletion of the EP300 gene is not caused by the administration of a BET inhibitor.

[0142] The mutation (e.g., a loss-of-function mutation or deletion in or within the EP300 gene) can be any acceptable mutation type, such as a substitution mutation, insertion mutation, deletion mutation, or a combination thereof. In some embodiments, the EP300 mutation is a substitution mutation. In some embodiments, the EP300 mutation is an insertion mutation. In some embodiments, the EP300 mutation is a deletion mutation. In some embodiments, the deletion mutation is a partial deletion mutation. In some embodiments, the deletion mutation is a complete deletion mutation. In some embodiments, the mutation may affect one copy of the gene. In some embodiments, the mutation may affect multiple copies of the gene.

[0143] Determining whether a tumor has an EP300 genetic mutation may include identifying the EP300 mutation in DNA extracted from a tumor sample and / or circulating tumor or tumor cell DNA. In some embodiments, the cancer is identified as containing the mutation (i.e., the cancer has been previously identified as containing the mutation) prior to the administration of a BET inhibitor.

[0144] A variety of tests can be used to detect EP300 mutations or deletions. For example, tests may include Sanger sequencing of the EP300 coding region amplified by PCR or next-generation sequencing (NGS) of the whole genome or captured / enriched EP300 coding region to sequence tumor DNA (e.g., by whole exome sequencing or sequencing of targeted mutation panels that include EP300 exons and introns).

[0145] Mutations can also be detected in RNA. These RNA mutations can be detected by sequencing cDNA derived from RNA using RNA-Seq or DNA methods. Furthermore, mutations can be detected by targeted amplification of variants and sequenced via next-generation sequencing (NGS) or by array-based genetic variant readout (e.g., using Illumina BeadArrays). Tumor DNA can be derived from biopsy samples or from cell-free DNA capture from indirect tumor sources, such as blood.

[0146] The function and amount of EP300 proteins can be determined by any acceptable method, including, for example, measuring the acetylation levels of proteins known to be modified by p300. Methods for quantifying these modifications can include Western blotting, mass spectrometry, protein binding arrays, or immunohistochemistry.

[0147] d. Improve the efficacy of cancer treatment The methods described in this article can be used to treat cancer, for example, by increasing cancer cell suppression or reducing cancer progression. "Increasing cancer cell suppression" can refer to reducing cancer cell activity or inhibiting cancer cell growth or proliferation.

[0148] In some implementations, administration of a BET inhibitor increases cancer cell suppression. In some implementations, administration of a BET inhibitor increases cancer cell suppression compared to other treatments. In some implementations, administration of a BET inhibitor increases cancer cell suppression in cancers including those with loss or deletion of the EP300 gene, compared to administration of the BET inhibitor to cancers without loss or deletion of function.

[0149] e. application The composition containing a BET inhibitor can be administered by any acceptable method, including, for example, parenteral administration. Acceptable parenteral administration methods include, but are not limited to, subcutaneous, intramuscular, and intravenous administration. In some embodiments, the method includes administering a BET inhibitor. In some embodiments, administration includes parenteral administration of a BET inhibitor. In some embodiments, the method includes administering a pharmaceutical composition containing a BET inhibitor (e.g., any pharmaceutical composition provided herein).

[0150] In some implementations, administration includes enteral administration of the BET inhibitor. Acceptable enteral administration methods include, but are not limited to, oral administration, gastric administration, and rectal administration.

[0151] In some implementations, application occurs once daily. In some implementations, application occurs twice daily. In some implementations, application occurs three times daily.

[0152] f. Pharmaceutical composition BET inhibitors (e.g., PLX-51107) can be delivered in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a BET inhibitor. The pharmaceutical composition can be used to treat cancer, such as any cancer disclosed herein (e.g., cancer identified as including loss or deletion of the EP300 gene). In some embodiments, the methods provided herein include determining the presence (e.g., in a subject) of a mutation or deletion of the EP300 gene.

[0153] The compositions described herein may comprise any suitable BET inhibitor, such as any BET inhibitor described herein. In some embodiments, the BET inhibitor is a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvation of the BET inhibitor described herein. In some embodiments, the pharmaceutical composition comprises a BET inhibitor and a pharmaceutically acceptable carrier (e.g., one or more pharmaceutically acceptable carriers, two or more pharmaceutically acceptable carriers, three or more pharmaceutically acceptable carriers, etc.). The carrier may be any acceptable or suitable carrier described herein. In some embodiments, the pharmaceutical composition comprising the BET inhibitor is administered in a method of treating a patient (e.g., involving loss or absence of EP300 function).

[0154] In some embodiments, the BET inhibitors described herein are administered as a pure chemical substance (i.e., not with excipients). In some embodiments, the BET inhibitors described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier), the pharmaceutically suitable or acceptable carrier being based on the chosen route of administration and, for example, in... Remington: The Science and Practice of Pharmacy The standard pharmaceutical practice selection described in (Gennaro, 21st edition. MackPub. Co., Easton, PA (2005)).

[0155] In some embodiments, the pharmaceutical composition containing a BET inhibitor is formulated for oral administration. Suitable oral dosage forms include, but are not limited to, tablets, pills, sachets, or capsules.

[0156] In some embodiments, the pharmaceutical composition containing a BET inhibitor is formulated for injection. In some cases, the injectable formulation is an aqueous formulation. In some cases, the injectable formulation is a non-aqueous formulation. In some cases, the injectable formulation is an oil-based formulation, such as sesame oil.

[0157] The dosage of compositions containing BET inhibitors can vary depending on the subject or patient's condition. Such considerations may include general health status, age, and other factors.

[0158] The pharmaceutical compositions described herein can be administered in any manner suitable for the treatment or prevention of a disease (e.g., cancer). Appropriate dosage and suitable duration and frequency of administration can be determined based on factors relevant to the patient's condition, such as the type and severity of the patient's disease, the patient's age, weight, body surface area, etc. Alternatively, appropriate dosage and suitable duration and frequency of administration can be determined based on factors relevant to the composition, such as the specific form of the active ingredient and the method of administration. In some cases, appropriate dosage is determined by factors relevant to both the patient's condition and the composition. Generally, appropriate dosage and treatment regimens can be provided in an amount sufficient to provide therapeutic and / or preventive benefits (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival). Optimal dosage is typically determined using experimental models and / or clinical trials. Optimal dosage can depend on the patient's body mass, weight, or blood volume.

[0159] II. Kits for treating cancer In some implementations, this document further provides kits for treating cancer, including tests for determining loss or absence of function of the EP300 gene. In some embodiments, the BET inhibitors include ABBV-075, ABBV-744, apatadone, APL-581, ARV-825, AZD-5153, BI-6727, BI-894999, BMS-986158, BOS-475, BPI-23314, CD-161, CG-223, CK-103, CN-470, FT-1101, GNE-0011, GS-5829, GS-626510, GSK525762, I-BET151, INCB054329, INCB57643, JQ1LY-294002, NEO2734, ODM-207, OMT-001, OMT-002, OTX-015, Pelabresib, and PLX-2853. (OPN-2853), PLX-51107 (OPN-51107), TEN-010, RVX-297, SRX-2523, SRX-3225, SRX-3254, SW-064652, SYHA-1801, TTI-281, Zen-3694, CPI-0610, INCB0543294, JAB-8263, INCB057643, CC-90010, Arobresib, GSK778, GSK046, Mivibusib, Trobaresib, Molibresib, Pelabresib, or combinations thereof. In some embodiments, the BET inhibitor includes AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, INCB57643, OTX-015, PLX-51107, or combinations thereof. In some embodiments, the BET inhibitor includes AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, OTX-015, PLX-51107, INCB057643, TEN-010, CC-90010, arobuxare, ODM-207, GSK778, GSK046, ABBV-744, mivebuxil, trotabresib, molibresib, pilarresib, pelabresib, or combinations thereof. In some embodiments, the BET inhibitor is OTX-015, PLX-51107, PLX-2853, or a combination thereof. In some embodiments, the BET inhibitor is JAB-8263. In some embodiments, the BET inhibitor includes AZD-5153.In some embodiments, the BET inhibitor comprises BI-894999. In some embodiments, the BET inhibitor comprises BMS-986158. In some embodiments, the BET inhibitor comprises GSK525762. In some embodiments, the BET inhibitor comprises INCB054329. In some embodiments, the BET inhibitor comprises TEN-010. In some embodiments, the BET inhibitor comprises PLX-51107. In some embodiments, the BET inhibitor comprises PLX-2853. In some embodiments, the BET inhibitor comprises OTX-015. In some embodiments, the BET inhibitor comprises JAB-8263. In some embodiments, the BET inhibitor comprises INCB057643. In some embodiments, the BET inhibitor comprises CC-90010. In some embodiments, the BET inhibitor comprises arobuxostat. In some embodiments, the BET inhibitor comprises ODM-207. In some embodiments, the BET inhibitor comprises GSK778. In some embodiments, the BET inhibitor comprises GSK046. In some embodiments, the BET inhibitor comprises ABBV-744. In some embodiments, the BET inhibitor comprises mirabresib. In some embodiments, the BET inhibitor comprises Trobaresib. In some embodiments, the BET inhibitor comprises Molibresib. In some embodiments, the BET inhibitor comprises pilaresib. In some embodiments, the BET inhibitor comprises Pelabresib. In some embodiments, the BET inhibitor comprises a compound of formula IV. In some embodiments, the BET inhibitor comprises compound 5. In some embodiments, the BET inhibitor comprises compound 9.

[0160] In some embodiments, the cancer includes breast cancer, urothelial carcinoma, rectal cancer, thymic carcinoma, sarcoma, or combinations thereof. In some embodiments, the urothelial carcinoma includes bladder cancer. In some embodiments, the methods provided herein include determining the presence (e.g., in a subject) of a mutation or deletion in the EP300 gene.

[0161] definition As used in the specification and appended claims, unless otherwise stated, the following terms have the meanings indicated below.

[0162] Unless the context explicitly requires otherwise, the singular forms (e.g., "a," "and," and "the") include plural referents. Thus, for example, reference to "an agent" includes multiple such agents, and reference to "the cell" includes reference to one or more cells (or multiple cells) and their equivalents known to those skilled in the art, and so on. When the scope is used herein to refer to physical properties (such as molecular weight) or chemical properties (such as chemical formula), it should include the scope and all combinations and sub-combinations of the specific embodiments therein.

[0163] When the term “about” refers to a number or range of values, it means that the number or range of values ​​mentioned is an approximation within experimental variability (or statistical experimental error), and therefore also refers to that number or range of values. In some cases, the term “about” preceding a given value includes that given value, and also includes ±20% of that given value or range, and more specifically includes ±10%, ±5%, ±2%, and ±1% of that given value or range.

[0164] In the context of a disease, a substance, or the activity or function of a substance related to a disease, the term “related” or “associated with” means that the disease is caused (wholly or partially) by the substance or its activity or function, that the symptoms of the disease are caused (wholly or partially) by the substance or its activity or function, or that the side effects (such as toxicity) of a compound are caused (wholly or partially) by the substance or its activity or function.

[0165] The term “comprising” (and related terms such as “comprise”, “comprises”, “having”, or “including”) does not mean that an embodiment of any substance composition, composition, method, or process described herein is “constituted” or “substantially constituted” by the described features.

[0166] "Disease" or "condition" refers to the state or health status of a patient or subject who can be treated with the compounds or methods provided herein. In some embodiments, as used herein, disease refers to cancer.

[0167] As defined herein, when referring to protein-inhibitor interactions, the terms “inhibition,” “inhibit,” and “inhibiting” refer to a negative impact (e.g., a reduction) on the activity or function of a protein (e.g., BET) relative to the absence of an inhibitor. Therefore, inhibition includes at least partially or completely blocking stimulation, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating the activity or amount of signal transduction or enzymes or proteins. In this context, inhibition and such terms can refer to the reduction of disease or disease symptoms.

[0168] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus producing enantiomers, diastereomers, and other stereoisomers, which are defined in absolute stereochemistry as ( R )or( S Unless otherwise stated, this disclosure is intended to cover all stereoisomers of the compounds disclosed herein. When the compounds described herein contain an alkene double bond, unless otherwise stated, this disclosure is intended to include... E and Z Two geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomers, are intended to be included. The term "geometric isomer" refers to the isomer of the olefin double bond. E or Z Geometric isomers (e.g., cis or trans). The term "positional isomers" refers to structural isomers around the central ring, such as the ortho, meta, and para isomers around the benzene ring.

[0169] As used herein, “delayed disease development” means postponing, hindering, slowing, delaying, stabilizing, and / or deferring the development of a disease (such as cancer). The length of such delay can vary depending on the individual’s medical history and / or treatment. It will be apparent to those skilled in the art that a sufficient or significant delay can effectively cover prevention, as the individual will not develop the disease. For example, the development of advanced cancer (such as metastasis) can be delayed.

[0170] The terms "selective" or "selective," "specific," "specifically," "specifically," etc., used to describe a compound refer to its ability to induce a particular effect or to distinguish between molecular targets, such as the inhibition of a specific molecular target (e.g., BD2). For example, in cells, a selective BD2 inhibitor may have at least 3x higher selectivity for BD2 compared to BD1. As a further example, a selective BET inhibitor may have at least 3x higher selectivity for BET compared to other targets in cells (e.g., Plk1).

[0171] As used herein, compounds that provide inhibitory properties (e.g., BET inhibitors) include small molecule compounds and biological products (e.g., those derived from living materials (e.g., antibodies, proteins, peptide fragments, etc.) unless the context clearly specifies otherwise.

[0172] A "tautomer" is a molecule in which a proton can be transferred from one atom of the molecule to another atom of the same molecule. In some embodiments, the compounds presented herein exist as tautomers. Where tautomerism is possible, a chemical equilibrium of tautomers will exist. The exact proportions of tautomers depend on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include: "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. The pharmaceutically acceptable salt of any BET inhibitor described herein is intended to include any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0173] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free base, are not adverse in biological or other respects, and are formed from inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc.). It also includes salts formed from the following organic acids: for example, aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate caprylates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Salts of amino acids, such as arginine salts, gluconates, and galacturons (e.g., see Berge SM et al., "Pharmaceutical Salts"), are also considered. Journal of Pharmaceutical Science, 66:1-19 (1997). In some embodiments, the acid addition salt of the basic compound is prepared by contacting a sufficient amount of the desired acid with a free base form to produce the salt, according to methods and techniques familiar to those skilled in the art.

[0174] "Pharmaceutically acceptable base addition salts" refer to salts that retain the bioavailability and properties of the free acid and are not adverse in biological or other respects. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed from metals or amines, such as alkali metals and alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, etc. N,N- Dibenzylethylenediamine, chloroprocaine, heparin, choline, betaine, ethylenediamine, ethylenediphenylamine N -Methylglucosamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al. above.

[0175] "Pharmaceutically acceptable solvates" refer to substances in the form of solvent addition. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of solvent and is formed during preparation using pharmaceutically acceptable solvents (such as water, ethanol, etc.). When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcohol is formed. The solvates of the compounds described herein are conveniently prepared or formed in the processes described herein. The compounds provided herein exist in unsolvated or solvated forms.

[0176] The terms “object,” “individual,” or “patient” include mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees, and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one respect, a mammal is a human.

[0177] As used herein, “mutation” can refer to a change in a polynucleotide sequence that results in a change in protein function. Changes in protein function can occur through changes in the protein encoded by the polynucleotide sequence. Changes in protein function can be altered by changes in the amino acid sequence of the protein or protein quantity (e.g., expression level) or both. Mutations can be nucleotide substitutions, such as single nucleotide substitutions, insertions, or deletions, and can ultimately alter the splicing of messenger RNA (mRNA), the level of mRNA, and / or the amino acid sequence of the protein encoded by said mRNA. Mutations can also occur in regions that regulate protein expression levels or processing.

[0178] As used herein, “loss of function” may be due to 1) changes in the amino acid sequence that result in the loss or reduction of one or more normal functions of the protein, or 2) a reduction in the amount of EP300 protein. These changes may be caused by: genetic alterations (changes in genomic DNA), changes in normal mRNA production and processing (e.g., through alterations in splicing, or through changes in gene expression regulation (e.g., mutations in gene regulatory regions or silencing gene expression via epigenetic silencing), and / or changes in protein translation that result in errors in protein sequence synthesis or abnormal protein folding.

[0179] As used herein, the terms “treatment,” “treating,” “relief,” or “improvement” are used interchangeably. These terms refer to methods of achieving a beneficial or desired outcome, including but not limited to therapeutic and / or preventative benefits. The term “therapeutic benefit,” etc., can include eradication or improvement of the underlying condition being treated. Furthermore, a therapeutic benefit can be achieved by eradicating or improving one or more symptoms associated with the underlying condition, resulting in an improvement that can be observed in a patient, even though the patient may still have the underlying condition. To achieve a preventative benefit, the composition can be administered to patients at risk of developing a specific disease, or to patients who report one or more physiological symptoms of a disease, even if the disease has not yet been diagnosed.

[0180] Example While preferred embodiments of this disclosure have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Numerous variations, modifications, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments described herein may be employed in carrying out the invention. The appended claims are intended to define the scope of the invention and thereby cover the methods and structures within the scope of these claims and their equivalents.

[0181] Example 1 - Identification of EP300 gene mutation Experiments were conducted to identify potential loss-of-function mutations and deletions in EP300. Genomic DNA was extracted from FFPE-preserved tumor biopsy tissue. Targeted capture was used to enrich the exome, including all coding exons. NGS libraries were constructed and indexed using the Illumina TruSeq Exome Kit (catalog number 20020614), followed by sequencing on the Illumina HiSeq platform. Somatic mutations were then identified (e.g., according to the methods described in PMID 24192750 or PMID 33106175). Genomic variants (SNVs and insertions / deletions) were identified using GATK (PMID 20644199), and somatic mutations were identified using Mutect2 (PMID 23396013) and Varscan (PMID 19542151). Based on changes in amino acid substitutions or protein coding, mutations are filtered into functional / destructive mutations. The predicted functional effect is inferred using MutationTaster (PMID 20676075), the "destructive" marker is inferred using SIFT (PMID 12824425), and / or the "potentially harmful" marker is inferred using Polyphen-2 (PMID 23315928). Loss-of-function (LOF) mutations may include hotspot mutations.

[0182] Superficial (e.g., single-copy loss) and deep deletions (e.g., which may include complete (zero-copy) loss of one or more regions of EP300 overlapping with a portion or the entire coding exon) can also constitute EP300LOF events. Deletion and complete loss of the EP300 gene were determined from exome data using Control-FREEC (PMID 22155870). Western spectroscopy and immunohistochemistry were performed on FFPE-preserved tumor biopsies to confirm reduced or lost EP300 gene expression at the protein level.

[0183] Example 2 - Frequency of EP300 Changes in Various Cancers The estimated frequencies of some EP300 loss-of-function events in various cancers from the GENIE project (Genomics Evidence Neoplasia Information Exchange) are shown in Table 1 below.

[0184] Table 1 Example 3. Cell assay To investigate the effects of BET inhibitors on cells with the EP300 LOF mutation, cells with and without the EP300 LOF mutation were treated with BET inhibitors.

[0185] Isogenetic pairs were generated for cancer cell lines that differed only in the EP300 mutation state (with and without EP300 loss of function). The Synthego CRISPR gene knockout v2 kit was used to knock out EP300 in KP4 cells (where EP300 was wild-type and present in 2 copies; PMID 23550210). EP300 knockout was confirmed by Sanger sequencing and Synthego analysis software. Cells were seeded in triplicate at 2000 cells / well in 96-well plates and treated with different concentrations of BET inhibitors ranging from 50 μM to sub-nanomolar concentrations across a 3x dilution gradient. Cell viability was determined by CellTiterGlo 4–11 days after treatment initiation.

[0186] The curves show a dose-dependent response to BET inhibitors, with higher concentrations leading to a more significant decrease in cell viability and greater overall sensitivity in EP300 knockout cells (i.e., lower concentrations of the drug resulted in the same decrease in viability in EP300-LOF as in EP300 wt).

[0187] Figure 1- Figure 9 The inhibitory effects of various compounds on different cell lines with wild-type EP300 or EP300 knockout were demonstrated. As shown in these figures, cell lines with the EP300 LOF mutation exhibited higher sensitivity to a variety of BET inhibitors. Figure 1A-Figure 1B The role of AZD-5153 in cancer cells with wild-type EP300 and EP300 knockout was described. Figure 1A The role of AZD-5153 in the lung cancer cell line H2009 was described, and Figure 1B The role of AZD-5153 in the bladder cancer cell line SW780 was described.

[0188] Figures 2A-2B The role of BI-2536 in cancer cells with wild-type EP300 and EP300 knockout was described. Figure 2A The role of BI-2536 in the bladder cancer cell line SW780 was described, and Figure 2B The role of BI-2536 in the pancreatic cancer cell line KP4 was described.

[0189] Figure 3 The role of BI-894999 in wild-type EP300 and EP300 knockout KP4 pancreatic cancer cells was described.

[0190] Figures 4A-4B The role of BMS-986158 in cancer cells with wild-type EP300 and EP300 knockout was described. Figure 4A The role of BMS-986158 in the bladder cancer cell line SW780 was described, and Figure 4B The role of BMS-986158 in the pancreatic cancer cell line KP4 was described.

[0191] Figures 5A-5B The role of GSK525762 in cancer cells with wild-type EP300 and EP300 knockout was described. Figure 5A The role of GSK525762 in the bladder cancer cell line SW780 was described, and Figure 5B The role of GSK525762 in the pancreatic cancer cell line KP4 was described.

[0192] Figure 6 The role of INCB054329 in wild-type EP300 and EP300 knockout KP4 pancreatic cancer cells was described.

[0193] Figures 7A-7D The role of OTX-015 in cancer cells with wild-type EP300 and EP300 knockout was described. Figure 7A The role of OTX-015 in the bladder cancer cell line RT11284 was described. Figure 7B The role of OTX-015 in the pancreatic cancer cell line KP4 was described.

[0194] Figure 7C The role of OTX-015 in the bladder cancer cell line SW780 was described. Figure 7D The role of OTX-015 in the lung cancer cell line Calu1 was described.

[0195] Figures 8A-8C The role of PLX-51107 in cancer cells with wild-type EP300 and EP300 knockout was described. Figure 8A The role of PLX-51107 in the bladder cancer cell line RT11284 was described. Figure 8B The role of PLX-51107 in the lung cancer cell line Calu1 was described. Figure 8C The role of PLX-51107 in the pancreatic cancer cell line KP4 was described.

[0196] Figure 9 The role of TEN-010 in KP4 pancreatic cancer cells with wild-type EP300 and EP300 knockout was described. Figure 10The role of JQ1 in KP4 pancreatic cells with wild-type EP300 and EP300 knockout was described.

[0197] The results of this experiment indicate that for drugs whose main targets include BRD2, BRD3 and / or BRD4, there is synthetic lethality between BET inhibitors and EP300 loss-of-function mutations.

[0198] Example 4. Xenograft research using patient-derived xenograft models. To investigate the potential of treating tumors with EP300-LOF using BET inhibitors such as PLX-51107 and piracetam, patient-derived xenograft (PDX) models with predicted LOF mutations in EP300 were identified from the NCI Patient Derived Model Repository (PDMR) at Jackson Labs (JAX). Whole-exome sequencing data were analyzed using, for example, the methods described in Example 1 to identify LOF EP300 mutations. GATK and Samtools were used to determine possible somatic single nucleotide variants (SNVs) and insertions / deletions, which were then filtered based on the high probability of inducing changes in protein function, and further differentiated from gain-of-function (GOF) mutations based on their absence in sequence or structural hotspot regions.

[0199] PDX samples carrying the EP300 LOF mutation, selected using the above criteria, were cut into uniform sizes and subcutaneously implanted into the bilateral flanks of 5-week-old JAX-derived NSG mice. A 3x8 experimental design (3 treatments, 8 replicates) was used for each study (i.e., each model). Tumors were measured every other day until the tumor volume reached approximately 150 mm. 3 BET inhibitors are administered orally by gavage once daily (1-20 mg / kg). Tumor size is recorded daily, and body weight is measured every 7 days to monitor drug toxicity. Tumor volume is calculated using the following formula: Tumor volume (mm3) = 1 / 2 (W)² x (L). Once the tumor reaches 500 mm... 3 Mice were then euthanized. Differences were determined by log-rank Kaplan-Meier survival analysis or by comparing growth kinetics over time.

[0200] Mice carrying the EP300-LOF mutant PDX model experienced a significant reduction in tumor growth after oral treatment with PLX-51107 or piracetam at a dose of 20 mg / kg. Figure 11 No significant changes in body weight were observed in mice treated with PLX-51107 or piracetam. Figure 12 ).

[0201] Example 5. Xenograft studies of compounds of formula VII (e.g., compound 9) using patient-derived xenograft models. To investigate the potential of using a compound of formula VII (e.g., compound 9) to treat tumors with EP300-LOF, the technique described in Example 4 (“Xenograft Study Using a Patient-Derived Xenograft Model”) will be employed, using concentrations of compound of formula VII (e.g., compound 9) modeled for clinically meaningful exposure levels.

[0202] Mice carrying the EP300-LOF mutant PDX model were treated orally with a compound of formula VII (e.g., compound 9). The treated mice achieved a significant reduction in tumor growth without significant weight loss.

[0203] Example 6. Patient Selection Tumor-derived FFPE biopsy samples were used to identify subjects with EP300 LOF. Next-generation sequencing (NGS) was performed on target gene sets containing all exons of EP300 to generate sequencing data. Mutations were determined using the method described in Example 1.

[0204] Example 7. Cell assay To investigate the effects of BET inhibitors on cells with the EP300 LOF mutation, cells with and without the EP300 LOF mutation were treated with BET inhibitors.

[0205] Isogenetic pairs were generated for cancer cell lines that differed only in the EP300 mutation state (with and without EP300 loss of function). The Synthego CRISPR gene knockout v2 kit was used to knock out EP300 in KP4 cells (where EP300 was wild-type and present in 2 copies; PMID 23550210). EP300 knockout was confirmed by Sanger sequencing and Synthego analysis software. Cells were seeded in triplicate at 2000 cells / well in 96-well plates and treated with different concentrations of BET inhibitors ranging from 50 μM to sub-nanomolar concentrations across a 3x dilution gradient. Cell viability was determined by CellTiterGlo 4–11 days after treatment initiation.

[0206] The curves will show the dose-dependent response to BET inhibitors, with higher concentrations leading to a more significant decrease in cell viability and greater overall sensitivity in EP300 knockout cells (i.e., lower concentrations of the drug result in the same decrease in viability in EP300-LOF as in EP300 wt).

[0207] Figures 13-44The inhibitory effects of various compounds on different cell lines with wild-type EP300 or EP300 knockout were demonstrated. As shown in these figures, cell lines with the EP300 LOF mutation exhibited higher sensitivity to a variety of BET inhibitors.

[0208] Figure 13 The role of AZD-5153 in H2009 lung cancer cell lines with wild-type EP300 and EP300 knockout was described.

[0209] Figure 14 The role of TEN-010 in KP4 pancreatic cancer cells with wild-type EP300 and EP300 knockout was described.

[0210] Figures 15-17 The role of INCB057643 in cancer cells with wild-type EP300 and EP300 knockout was described. Figure 15 The role of INCB057643 in wild-type EP300 and EP300 knockout KP4 pancreatic cancer cells was described. Figure 16 The role of INCB057643 in SW780 bladder cancer cells with wild-type EP300 and EP300 knockout was described. Figure 17 The role of INCB057643 in HCC827 lung cancer cells with wild-type EP300 and EP300 knockout was described.

[0211] Figure 18 The role of CC-90010 in wild-type EP300 and EP300 knockout KP4 pancreatic cancer cells was described.

[0212] Figure 19 The effects of BI-2536 in wild-type EP300 and EP300 knockout KP4 pancreatic cancer cells were described. BI-2536 is a potent Plk1 inhibitor with a selectivity for Plk1 >40x that for BRD4. BI-2536 was included as a negative control, and it demonstrated the effectiveness of BET inhibitors in synthetic lethality compared to Plk1 inhibitors.

[0213] Figures 20-22 The role of PLX-51107 in cancer cells with wild-type EP300 and EP300 knockout was described. Figure 20 The role of PLX-51107 in KP4 pancreatic cancer cells with wild-type EP300 and EP300 knockout was described. Figure 21 The role of PLX-51107 in Calu1 lung cancer cells with wild-type EP300 and EP300 knockout was described. Figure 22The role of PLX-51107 in SW780 bladder cancer cells with wild-type EP300 and EP300 knockout was described.

[0214] Figures 23-24 The role of arobuxostat in cancer cells with wild-type EP300 and EP300 knockout was described. Figure 23 The role of arobuxostat in Calu1 lung cancer cells with wild-type EP300 and EP300 knockout was described. Figure 24 The role of arobuxostat in wild-type EP300 and EP300 knockout KP4 pancreatic cancer cells was described.

[0215] Figure 25 The role of ODM-207 in KP4 pancreatic cancer cells with wild-type EP300 and EP300 knockout was described.

[0216] Figures 26-27 The role of GSK778 in cancer cells with wild-type EP300 and EP300 knockout was described. Figure 26 The role of GSK778 in wild-type EP300 and EP300 knockout KP4 pancreatic cancer cells was described. Figure 27 The role of GSK778 in Calu1 lung cancer cells with wild-type EP300 and EP300 knockout was described.

[0217] Figure 28 The role of GSK046 in wild-type EP300 and EP300 knockout KP4 pancreatic cancer cells was described.

[0218] Figures 29-30 The role of ABBV-744 in cancer cells with wild-type EP300 and EP300 knockout was described. Figure 29 The role of ABBV-744 in Calu1 lung cancer cells with wild-type EP300 and EP300 knockout was described. Figure 30 The role of ABBV-744 in wild-type EP300 and EP300 knockout KP4 pancreatic cancer cells was described.

[0219] Figure 31 The role of compound 5 in KP4 pancreatic cancer cells with wild-type EP300 and EP300 knockout was described.

[0220] Figure 32 The role of mivibusser in wild-type EP300 and EP300 knockout KP4 pancreatic cancer cells was described.

[0221] Figure 33The role of ZEN-3694 in wild-type EP300 and EP300 knockout KP4 pancreatic cancer cells was described.

[0222] Figure 34 The role of Trotabresib in KP4 pancreatic cancer cells with wild-type EP300 and EP300 knockout was described.

[0223] Figures 35-36 The effects of Molibresib in cancer cells with wild-type EP300 and EP300 knockout were described. Figure 35 The role of Molibresib in KP4 pancreatic cancer cells with wild-type EP300 and EP300 knockout was described. Figure 36 The role of Molibresib in SW780 bladder cancer cells with wild-type EP300 and EP300 knockout was described.

[0224] Figures 37-40 The role of bilarase in cancer cells with wild-type EP300 and EP300 knockout was described. Figure 37 The role of bilarose in Calu1 lung cancer cells with wild-type EP300 and EP300 knockout was described. Figure 38 The role of bilarose in wild-type EP300 and EP300 knockout KP4 pancreatic cancer cells was described. Figure 39 The role of bilarose in wild-type EP300 and EP300 knockout SW780 bladder cancer cells was described. Figure 40 The role of bilarase in SW1271 lung cancer cells with wild-type EP300 and EP300 knockout was described.

[0225] Figure 41 The role of INCB054329 in wild-type EP300 and EP300 knockout KP4 pancreatic cancer cells was described.

[0226] Figure 42 The role of BI-894999 in wild-type EP300 and EP300 knockout KP4 pancreatic cancer cells was described.

[0227] Figure 43 The role of Pelabresib in KP4 pancreatic cancer cells with wild-type EP300 and EP300 knockout was described.

[0228] Figure 44 The role of C177 (JQ1) in pancreatic cancer cells KP4 with wild-type EP300 and EP300 knockout was described.

[0229] The results of this experiment indicate that for drugs whose main targets include BRD2, BRD3 and / or BRD4, there is synthetic lethality between BET inhibitors and EP300 loss-of-function mutations.

[0230] Example 8. Xenograft research using patient-derived xenograft models To investigate the potential of using BET inhibitors such as PLX-51107 and piracetam for the treatment of tumors with EP300-LOF, patient-derived xenograft (PDX) models with predicted LOF mutations in EP300 were identified from the NCI Patient-Derived Model Library (PDMR) and at Jackson Labs (JAX). For these experiments, PDX model J000108112 ( Figures 46A-46D ) and TM00244 ( Figures 47A-47D Whole-exome sequencing data were analyzed using, for example, the method described in Example 1, to identify LOF EP300 mutations. GATK and Samtools were used to identify possible somatic single nucleotide variants (SNVs) and insertions / deletions, which were then filtered based on the high probability of inducing changes in protein function, and further distinguished from gain-of-function (GOF) mutations based on their absence in sequence or structural hotspot regions.

[0231] PDX samples carrying the EP300 LOF mutation, selected using the above criteria, were cut into uniform sizes and subcutaneously implanted into the bilateral flanks of 5-week-old JAX-derived NSG mice. A 3x8 experimental design (3 treatments, 8 replicates) was used for each study (i.e., each model). Tumors were measured every other day until the tumor volume reached approximately 150 mm. 3 BET inhibitors are administered orally by gavage once daily (20 mg / kg). Tumor size is recorded daily, and body weight is measured every 7 days to monitor drug toxicity. Tumor volume is calculated using the following formula: Tumor volume (mm3) = 1 / 2 (W)² x (L). Once the tumor reaches 500 mm... 3 Mice were then euthanized. Differences were determined by log-rank Kaplan-Meier survival analysis or by comparing growth kinetics over time.

[0232] Mice carrying the EP300-LOF mutant PDX model J000108112, treated orally with PLX-51107 or piracetam, showed a significant reduction in tumor growth. Figure 46A No significant changes in body weight were observed in mice treated with PLX-51107 or piracetam. Figure 46B ).exist Figure 46C and Figure 46DThe images show the effects of PLX-51107 and piracetam treatment. Results demonstrated that the BET inhibitor reduced growth in the EP300-LOF mutant PDX model J000108112 mice.

[0233] Mice carrying the EP300-LOF mutant PDX model TM00244 were treated orally with PLX-51107 or piracetam, resulting in a significant reduction in tumor growth. Figure 47A No significant changes in body weight were observed in mice treated with PLX-51107 or piracetam. Figure 47B ).exist Figure 47C and Figure 47D The images show the effects of PLX-51107 and piracetam treatment. The results demonstrate that the BET inhibitor reduced growth in the EP300-LOF mutant PDX model TM00244 mice.

[0234] Example 9. CRISPR pharmacogenetic screening To investigate the role of synthetic lethality, CRISPR pharmacogenetic screening was conducted to study changes in cellular fitness when a given gene was knocked out and treated with a BET inhibitor (e.g., piracetam). In KP4 cells ( Figure 45A ) and MDAMB231 cells ( Figure 45B In this study, each gene knockout was accomplished using 3 to 4 different guide RNAs. A volcano plot was generated to depict the effect size and significance of driver gene perturbations in mixed CRISPR piracetam pharmacogenetic screening. Each circle (dot) in the plot represents a loss-of-function mutation (knockout) of a specific driver gene. Dots to the left of zero represent interactions where the presence of piracetam (but not the mediator control) leads to reduced fitness in cells with gene perturbations. The y-axis represents the significance of the interactions, taking into account both effect size and consistency between gene perturbations.

[0235] Figure 45A and Figure 45B The EP300 values ​​near the top left corner of both cells showed a strong and significant sensitization to β-Larrison. These results further demonstrate how synthetic lethality can occur between cells with loss-of-function mutations or deletions of EP300 and BET inhibitors.

[0236] Example 10. Cell assay using a compound of formula VII (e.g., compound 9) To investigate the effects of compound 9 on cells with the EP300 LOF mutation, cells with and without the EP300 LOF mutation were treated with a compound of formula (VII) (e.g., compound 9) using the technique described in Example 3. The results of this experiment will demonstrate synthetic lethality between compound (VII) (e.g., compound 9) and loss-of-function mutations or deletions of EP300.

[0237] The embodiments and implementations described herein are for illustrative purposes only, and any modifications or alterations that may be conceived by those skilled in the art will be included within the spirit and scope of this application and the appended claims.

Claims

1. A method for treating cancer in a subject in need, the method comprising administering a pharmaceutical composition to the subject, a. The pharmaceutical composition therein comprises a bromine domain and an additional terminal domain (BET) inhibitor; b. The cancer has been previously identified as involving loss or absence of function of the EP300 gene; c. The patient did not receive [the treatment] simultaneously. (Compound 1) or (Compound 2), and d. When the cancer is triple-negative breast cancer, the BET inhibitor is not JQ1.

2. A method for treating cancer in a subject in need, the method comprising administering a pharmaceutical composition to the subject, The pharmaceutical composition described herein contains an inhibitor of a bromine domain and an additional terminal domain (BET). The cancer has been previously identified as containing a reduced amount or activity of p300 compared to wild-type p300; The patient did not receive treatment at the same time. (Compound 1) or (Compound 2), and When the cancer is triple-negative breast cancer, the BET inhibitor is not JQ1.

3. The method of claim 1, wherein the loss of function is caused by a genetic mutation.

4. The method according to claim 1 or 2, wherein the object has not previously received compound 1 or compound 2.

5. The method according to any one of claims 1 to 4, wherein the BET inhibitor comprises ABBV-075, ABBV-744, apatadone, APL-581, ARV-825, AZD-5153, BI-6727, BI-894999, BMS-986158, BOS-475, BPI-23314, CD-161, CG-223, CK-103, CN- 470, FT-1101, GNE-0011, GS-5829, GS-626510, GSK525762, I-BET151, INCB054329, INCB576 43. JQ1, LY-294002, NEO2734, ODM-207, OMT-001, OMT-002, OTX-015, Pelabresib, PLX-2853 (OPN-2853), PLX-51107 (OPN-51107), TEN-010, RVX-297, SRX-2523, SRX-3225, SRX-3254, SW-064652, SYHA-1801, TTI-281, Zen-3694, CPI-0610, INCB0543294, INCB057643, CC-90010, Arobresib, GSK778, GSK046, Mivibusib, Trobaresib, Molibresib, Pelabresib, or combinations thereof.

6. The method according to claim 5, wherein the BET inhibitor comprises AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, INCB57643, OTX-015, PLX-51107, or a combination thereof.

7. The method according to claim 5, wherein the BET inhibitor comprises AZD-5153, BI-894999, BMS-986158, GSK525762, INCB054329, OTX-015, PLX-51107, INCB057643, TEN-010, CC-90010, arobuxe, ODM-207, GSK778, GSK046, ABBV-744, mivebuxe, trotabresib, molibresib, pilaroseib, pelabresib, or combinations thereof.

8. The method according to any one of claims 1 to 4, wherein the BET inhibitor comprises a compound of formula (I): Or its pharmaceutically acceptable salts, tautomers, stereoisomers, or deuterated analogs, wherein: R 1 It is a cyano, halogenated, or optionally substituted with one to three (C1-C3) alkyl groups independently selected from halogenated, methyl, ethyl, methoxy, and ethoxy groups; and When present, X is halogenated.

9. The method of claim 7, wherein R 1 It is (C1-C2) alkyl, cyano or fluorine.

10. The method of claim 9, wherein R 1 It is a methyl group.

11. The method of claim 9, wherein R 1 It's fluorine.

12. The method of claim 9, wherein R 1 It is a cyano group.

13. The method according to any one of claims 1 to 4, wherein the BET inhibitor comprises a compound of formula (II): Or its pharmaceutically acceptable salts, tautomers, stereoisomers, or deuterated analogs, wherein: R 1 It is an (C1-C3) alkyl group optionally substituted with 1 to 3 substituents independently selected from halogenated, methyl, ethyl, methoxy and ethoxy groups.

14. The method of claim 13, wherein R 1 It is a methyl group.

15. The method according to any one of claims 1 to 4, wherein the BET inhibitor comprises a compound of formula (III): Or its pharmaceutically acceptable salt, wherein: When present, X is halogenated.

16. The method according to any one of claims 1 to 4 and 7 to 15, wherein the BET inhibitor comprises compound 3: (Compound 3), or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

17. The method according to any one of claims 1 to 4, wherein the BET inhibitor comprises a compound having the formula (Va): Or its pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, or deuterated analogs. in: R 2 It is H; R 4 It is H; R 6 It is H; R 7 It is H, -OH, C 1-6 Alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; R 1 It is optional to be 1-3 R j heteroaryl groups substituted with functional groups; Each R j is independently selected from halogen, -CN, -OH, -NH2, -NO2, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -CH=C(R k )(R k )、-OR k 、-SR k 、-OC(O)R k 、-OC(S)R k 、-P(=O)HR k 、-P(=O)R k R k 、-PH(=O)OR k 、-P(=O)(OR k )2、-OP(=O)(OR k )2、-C(O)H、-O(CO)OR k 、-C(O)R k 、-C(S)R k 、-C(O)OR k 、-C(S)OR k 、-S(O)R k 、-S(O)2R k 、-C(O)NHR k 、-C(S)NHR k 、-C(O)NR k R k 、-C(S)NR k R k 、-S(O)2NHR k 、-S(O)2NR k R k 、-C(NH)N HR k 、-C(NH)NR k R k 、-NHC(O)R k 、-NHC(S)R k 、-NR k C(O)R k 、-NR k C(S)R k 、-NHS(O)2R k 、-NR k S(O)2R k 、-NHC(O)NHR k 、-NHC(S)NHR k 、-NR k C(O)NH2, -NR k C(S)NH2, -NR k C(O)NHR k , -NR k C(S)NHR k , -NHC(O)NR k R k , -NHC(S)NR k R k , -NR k C(O)NR k R k , -NR k C(S)NR k R k , -NHS(O)2NHR k , -NR k S(O)2NH2, -NR k S(O)2NHR k , -NHS(O)2NR k R k , -NR k S(O)2NR k R k , -NHR k or -NR k R k ; Each R k H and C independently 1-6 Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, or cycloalkylalkyl; or When bonded to the same carbon or nitrogen atom, two R k The groups together form a 3- to 6-membered carbon ring or a 3- to 8-membered heterocycle having 1-2 heteroatoms selected from O, N or S as ring members, wherein the nitrogen or sulfur ring atom is optionally oxidized; R 3 It is H, halogen, -CN, or optionally substituted C. 1-6 Alkyl groups, optionally substituted deuterated C 1-6 Alkyl, optionally substituted aryl, optionally substituted aryl-C 1-4 Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-C 1-4 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 cycloalkyl-C 1-4 Alkyl, optionally substituted heterocyclic alkyl, or optionally substituted heterocyclic alkyl-C 1-4 Alkyl; and R 5 It is optionally selected by one or two independent factors chosen from D, halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 R of halogenated alkoxy or -CN 11 Group substitution ； The wavy line indicates the connection point with the rest of the molecule.

18. The method of claim 17, wherein the BET inhibitor comprises compound 4: (Compound 4), or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

19. The method according to any one of claims 1 to 4, wherein the BET inhibitor comprises compound 9: (Compound 9) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

20. The method according to any one of the preceding claims, wherein the cancer includes bladder cancer, lung cancer, gynecological cancer, adrenocortical carcinoma, bone cancer, central nervous system (CNS) cancer, pancreatic cancer, gastrointestinal cancer, head and neck cancer, skin cancer, mesothelioma, schwannoma, lymphoma, renal cell carcinoma, salivary gland cancer, non-melanoma skin cancer, or combinations thereof.

21. The method according to any one of claims 1 to 20, wherein the cancer includes lung cancer.

22. The method of claim 21, wherein the lung cancer includes non-small cell lung cancer.

23. The method of claim 22, wherein the non-small cell lung cancer comprises squamous cell carcinoma, large cell carcinoma, adenocarcinoma, or a combination thereof.

24. The method of claim 23, wherein the non-small cell lung cancer includes squamous cell carcinoma.

25. The method of claim 23, wherein the non-small cell lung cancer includes large cell carcinoma.

26. The method of claim 23, wherein the non-small cell lung cancer includes adenocarcinoma.

27. The method of claim 21, wherein the lung cancer includes small cell lung cancer.

28. The method according to any one of claims 21 to 27, wherein the BET inhibitor comprises AZD-5153, INCB57643, OTX-015, PLX-51107, or a combination thereof.

29. The method according to any one of claims 1 to 20, wherein the cancer includes bladder cancer.

30. The method of claim 29, wherein the bladder cancer includes carcinoma.

31. The method of claim 30, wherein the cancer includes urothelial carcinoma.

32. The method according to any one of claims 29 to 31, wherein the BET inhibitor comprises AZD-5153, BMS-986158, GSK525762, INCB57643, OTX-015, PLX-51107, or a combination thereof.

33. The method according to any one of claims 1 to 20, wherein the cancer includes pancreatic cancer.

34. The method of claim 33, wherein the BET inhibitor comprises BI-894999, BMS-986158, GSK525762, INCB054329, INCB57643, OTX-015, PLX-51107, or a combination thereof.

35. The method of claim 20, wherein the skin cancer includes melanoma.

36. The method of claim 20, wherein the CNS cancer includes glioma.

37. The method of claim 20, wherein the CNS cancer comprises a neuroepithelial tumor.

38. The method of claim 20, wherein the lymphoma comprises non-Hodgkin lymphoma.

39. The method of claim 20, wherein the lymphoma comprises diffuse large B-cell lymphoma.

40. The method of claim 20, wherein the lymphoma comprises follicular lymphoma.

41. The method of claim 20, wherein the lymphoma comprises marginal zone lymphoma.

42. The method of claim 20, wherein the lymphoma comprises a mature B-cell tumor.

43. The method of claim 20, wherein the gastrointestinal cancer includes gastrointestinal stromal tumor, esophageal cancer, gastrointestinal neuroendocrine tumor, small bowel cancer, anal cancer, colon cancer, or a combination thereof.

44. The method of claim 20, wherein the gastrointestinal cancer includes gastrointestinal stromal tumor.

45. The method of claim 20, wherein the gastrointestinal cancer includes esophageal gastric cancer.

46. ​​The method of claim 20, wherein the gastrointestinal cancer includes a gastrointestinal neuroendocrine tumor.

47. The method of claim 20, wherein the gastrointestinal cancer includes small bowel cancer.

48. The method of claim 20, wherein the gastrointestinal cancer includes anal cancer.

49. The method of claim 20, wherein the gastrointestinal cancer includes colon cancer.

50. The method of claim 49, wherein the colon cancer includes colorectal cancer.

51. The method of claim 20, wherein the gynecological cancer includes cervical cancer.

52. The method of claim 20, wherein the gynecological cancer includes ovarian cancer.

53. The method of claim 20, wherein the gynecological cancer includes sex cord-stromal tumors.

54. The method of claim 20, wherein the gynecological cancer includes vaginal cancer.

55. The method of claim 20, wherein the cancer includes uterine cancer.

56. The method of claim 55, wherein the uterine cancer includes endometrial cancer or uterine sarcoma.

57. The method of claim 56, wherein the uterine cancer includes endometrial cancer.

58. The method of claim 57, wherein the endometrial cancer includes endometrial cancer of the uterine body.

59. The method of claim 55, wherein the uterine cancer includes uterine sarcoma.

60. The method of claim 59, wherein the uterine sarcoma includes uterine carcinosarcoma.

61. The method according to any one of the preceding claims, wherein the BET inhibitor inhibits any one or more of the following bromine domains: BRD2, BRD3, and BRD4.

62. The method of claim 61, wherein the BET inhibitor inhibits BRD4 and BRD2.

63. The method of claim 61, wherein the BET inhibitor inhibits BRD3 and BRD4.

64. The method of claim 61, wherein the BET inhibitor inhibits the BD1 bromodomain of BRD2, BRD3, BRD4 or any combination thereof.

65. The method of claim 61, wherein the BET inhibitor inhibits the BD2 bromodomain of BRD2, BRD3, BRD4 or any combination thereof.

66. The method according to any one of the preceding claims, wherein the BET inhibitor comprises a selective BET inhibitor.

67. The method of claim 66, wherein the selective BET inhibitor inhibits any one or more of the following bromine domains: BRD2, BRD3, and BRD4.

68. The method of claim 67, wherein the selective BET inhibitor is selective for BRD4 and BRD2.

69. The method of claim 67, wherein the selective BET inhibitor is selective for BRD2, BRD3 and BRD4.

70. The method of claim 67, wherein the selective BET inhibitor inhibits the BD1 bromodomain of BRD2, BRD3, BRD4, or any combination thereof.

71. The method of claim 70, wherein the selective BET inhibitor comprises GSK778.

72. The method of claim 67, wherein the selective BET inhibitor inhibits the BD2 bromodomain of BRD2, BRD3, BRD4, or any combination thereof.

73. The method of claim 72, wherein the selective BET inhibitor comprises GSK046, ABBV-744, compound 9, or any combination thereof.

74. The method according to any one of the preceding claims, wherein the loss or absence of function is targeted at the EP300 gene.

75. A method of treating cancer in a subject in need, the method comprising administering a pharmaceutical composition to the subject, a. The pharmaceutical composition therein comprises a bromine domain and an additional terminal domain (BET) inhibitor; b. The cancer has been previously identified as involving loss or absence of function of the EP300 gene; The BET inhibitors mentioned above include compounds of formula IV. Or its pharmaceutically acceptable salt or its stereoisomer. in: R1 is selected from hydrogen; deuterium; -C 1-6 Alkyl group; or -C3-8 carbon ring; and each of which, in each occurrence, is independently and optionally substituted by 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents, in each occurrence, is independently selected from deuterium, halogen, OH, -CN, -C 1-8 Alkyl, -C 1-8 Alkoxy, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2 or -C3-8 carbon ring; R2 is selected from hydrogen; deuterium; halogen; -OR 21 ;-NR 21 R 22 -CN; -SR 21 ;-SOR 21 ;-SO2R 21 ;-SO2NR 21 R 22 ;-C 1-8 alkyl; Carboxyl group; -COOR 21 ;-CONR 21 R 22 ;-NR 21 COR 22 ;-NR 21 SO2R 22 ; or -C 3_8 The carbon ring; and each of the rings is independently and optionally substituted by 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, -OH, -CN, -NH2, -C each time it appears. 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 Carbon rings or six-membered heterocycles containing one, two, or three heteroatoms selected from N or O; R 21 and R 22 Each of these terms is independently selected from hydrogen, deuterium, -OH, NH2, -CN, -C1-8 alkyl, -C1-8 alkoxy, -C1-8 alkylene-C 3-8 Carbon ring; or -C 3-8 Carbon rings; R 23 and R 24 Each of these elements is independently selected from hydrogen, deuterium, or -C each time it appears. 1-8 alkyl; A is selected from or ; Y1 is selected from N or CR Y1 ; Y2 is selected from O, S, and CR. Y1 R Y2 or NR Y2 ; R Y1 and R Y2 Each of these elements is independently selected from hydrogen, deuterium, halogen, -OH, NH2, -CN, -C1-6 alkyl, or -C each time it appears. 1-6 Alkoxy; Each of R3 and R4 is independently selected from hydrogen, deuterium, or -C each time it appears. 1-6 Alkyl groups; and each of them is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, -OH, -NH2, -CN, -C each time it appears. 1-6 Alkyl or -C 1-6 Alkoxy; n is selected from 0, 1, 2, 3, 4, 5, or 6; W1 is selected from hydrogen; deuterium; -F; -CI; -NH2; -CN; -OH; carboxyl group; -C 1-6 Alkyl; -C 1-6 Alkoxy; -C 1-3 Alkylene-C 1-3 Alkoxy; phenyl; a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N or O; a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N or O; a 3-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 4-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 5-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 6-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 3-membered carbon ring; a 4-membered carbon ring; a 5-membered carbon ring; or a 6-membered carbon ring; and each of these is independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents each time it appears, and each of these substituents is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, -C 1-3 Alkyl, or -C 1-3 Alkoxy; W2 is selected from hydrogen; deuterium; -F; -CI; -NH2; -CN; -OH; carboxyl group; -C 1-3 Alkyl; -C 1-3 Alkoxy; phenyl; naphthyl; 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 7-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 8-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 9-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 3-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; A 4-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 5-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 6-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 3-membered carbon ring; a 4-membered carbon ring; a 5-membered carbon ring; or a 6-membered carbon ring; and each of these is independently and optionally substituted with 1, 2, 3, 4, or 5 substituents each time it appears, and each of these substituents is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy each time it appears; Z is selected from hydrogen, deuterium, halogen, -NH2, -CN, -OH, carboxyl, -C1.6 alkyl, or -C 1-6 Alkyl group.

76. A method of treating cancer in a subject in need, the method comprising administering a pharmaceutical composition to the subject, The pharmaceutical composition described herein contains an inhibitor of a bromine domain and an additional terminal domain (BET). The cancer has been previously identified as containing a reduced amount or activity of p300 compared to wild-type p300; The BET inhibitors mentioned above include compounds of formula IV. Or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein: R1 is selected from hydrogen; deuterium; -C 1-6 Alkyl group; or -C3-8 carbon ring; and each of which, in each occurrence, is independently and optionally substituted by 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents, in each occurrence, is independently selected from deuterium, halogen, OH, -CN, -C 1-8 Alkyl, -C 1-8 Alkoxy, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, or -C3-8 carbon ring; R2 is selected from hydrogen; deuterium; halogen; -OR 21 ;-NR 21 R 22 -CN; -SR 21 ;-SOR 21 ;-SO2R 21 ;-SO2NR 21 R 22 ;-C 1-8 alkyl; Carboxyl group; -COOR 21 ;-CONR 21 R 22 ;-NR 21 COR 22 ;-NR 21 SO2R 22 ; or -C 3_8 The carbon ring; and each of the rings is independently and optionally substituted by 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, -OH, -CN, -NH2, -C each time it appears. 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 Carbon rings or six-membered heterocycles containing one, two, or three heteroatoms selected from N or O; R 21 and R 22 Each of these terms is independently selected from hydrogen, deuterium, -OH, NH2, -CN, -C1-8 alkyl, -C1-8 alkoxy, -C1-8 alkylene-C 3-8 Carbon ring; or -C 3-8 Carbon rings; R 23 and R 24 Each of these elements is independently selected from hydrogen, deuterium, or -C each time it appears. 1-8 alkyl; A is selected from or ; Y1 is selected from N or CR Y1 ; Y2 is selected from O, S, and CR. Y1 R Y2 or NR Y2 ; R Y1 and R Y2 Each of these elements is independently selected from hydrogen, deuterium, halogen, -OH, NH2, -CN, -C1-6 alkyl, or -C each time it appears. 1-6 Alkoxy; Each of R3 and R4 is independently selected from hydrogen, deuterium, or -C each time it appears. 1-6 Alkyl groups; and each of them is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, -OH, -NH2, -CN, -C each time it appears. 1-6 Alkyl or -C 1-6 Alkoxy; n is selected from 0, 1, 2, 3, 4, 5, or 6; W1 is selected from hydrogen; deuterium; -F; -CI; -NH2; -CN; -OH; carboxyl group; -C 1-6 Alkyl; -C 1-6 Alkoxy; -C 1-3 Alkylene-C 1-3 Alkoxy; phenyl; a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N or O; a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N or O; a 3-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 4-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 5-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 6-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 3-membered carbon ring; a 4-membered carbon ring; a 5-membered carbon ring; or a 6-membered carbon ring; and each of these is independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents each time it appears, and each of these substituents is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, -C 1-3 Alkyl, or -C 1-3 Alkoxy; W2 is selected from hydrogen; deuterium; -F; -CI; -NH2; -CN; -OH; carboxyl group; -C 1-3 Alkyl; -C 1-3 Alkoxy; phenyl; naphthyl; 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 7-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 8-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 9-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; 3-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; A 4-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 5-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 6-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, or S; a 3-membered carbon ring; a 4-membered carbon ring; a 5-membered carbon ring; or a 6-membered carbon ring; and each of these is independently and optionally substituted with 1, 2, 3, 4, or 5 substituents each time it appears, and each of these substituents is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy each time it appears; Z is selected from hydrogen, deuterium, halogen, -NH2, -CN, -OH, carboxyl, -C1.6 alkyl, or -C 1-6 Alkyl group.

77. The method of claim 75, wherein the loss of function is caused by a genetic mutation.

78. The method according to claim 75 or 76, wherein the BET inhibitor comprises compound 5: (Compound 5) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

79. The method according to claim 75 or 76, wherein the BET inhibitor comprises compound 6: (Compound 6) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

80. The method according to claim 75 or 76, wherein the BET inhibitor comprises compound 7: (Compound 7) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

81. The method according to claim 75 or 76, wherein the BET inhibitor comprises compound 8: (Compound 8) Or a pharmaceutically acceptable salt, tautomer, solvate, or deuterated analogue thereof.

82. The method according to claim 75 or 76, wherein the cancer includes bladder cancer, lung cancer, gynecological cancer, adrenocortical carcinoma, bone cancer, central nervous system (CNS) cancer, pancreatic cancer, gastrointestinal cancer, head and neck cancer, skin cancer, mesothelioma, schwannoma, lymphoma, renal cell carcinoma, salivary gland cancer, non-melanoma skin cancer, or combinations thereof.

83. The method of claim 82, wherein the cancer includes lung cancer.

84. The method of claim 83, wherein the lung cancer includes non-small cell lung cancer.

85. The method of claim 84, wherein the non-small cell lung cancer comprises squamous cell carcinoma, large cell carcinoma, adenocarcinoma, or a combination thereof.

86. The method of claim 85, wherein the non-small cell lung cancer includes squamous cell carcinoma.

87. The method of claim 85, wherein the non-small cell lung cancer includes large cell carcinoma.

88. The method of claim 85, wherein the non-small cell lung cancer comprises adenocarcinoma.

89. The method of claim 84, wherein the lung cancer comprises small cell lung cancer.

90. The method of claim 82, wherein the cancer includes bladder cancer.

91. The method of claim 90, wherein the bladder cancer includes carcinoma.

92. The method of claim 91, wherein the cancer includes urothelial carcinoma.

93. The method of claim 82, wherein the cancer comprises pancreatic cancer.

94. The method of claim 82, wherein the skin cancer includes melanoma.

95. The method of claim 82, wherein the CNS cancer includes glioma.

96. The method of claim 82, wherein the CNS cancer comprises a neuroepithelial tumor.

97. The method of claim 82, wherein the lymphoma comprises non-Hodgkin lymphoma.

98. The method of claim 82, wherein the lymphoma comprises diffuse large B-cell lymphoma.

99. The method of claim 82, wherein the lymphoma comprises follicular lymphoma.

100. The method of claim 82, wherein the lymphoma comprises marginal zone lymphoma.

101. The method of claim 82, wherein the lymphoma comprises a mature B-cell tumor.

102. The method of claim 82, wherein the gastrointestinal cancer includes gastrointestinal stromal tumor, esophageal cancer, gastrointestinal neuroendocrine tumor, small bowel cancer, anal cancer, colon cancer, or a combination thereof.

103. The method of claim 82, wherein the gastrointestinal cancer includes gastrointestinal stromal tumor.

104. The method of claim 82, wherein the gastrointestinal cancer includes esophageal gastric cancer.

105. The method of claim 82, wherein the gastrointestinal cancer includes a gastrointestinal neuroendocrine tumor.

106. The method of claim 82, wherein the gastrointestinal cancer includes small bowel cancer.

107. The method of claim 82, wherein the gastrointestinal cancer includes anal cancer.

108. The method of claim 82, wherein the gastrointestinal cancer includes colon cancer.

109. The method of claim 108, wherein the colon cancer includes colorectal cancer.

110. The method of claim 82, wherein the gynecological cancer includes cervical cancer.

111. The method of claim 82, wherein the gynecological cancer includes ovarian cancer.

112. The method of claim 82, wherein the gynecological cancer includes sex cord-stromal tumors.

113. The method of claim 82, wherein the gynecological cancer includes vaginal cancer.

114. The method of claim 82, wherein the cancer includes uterine cancer.

115. The method of claim 114, wherein the uterine cancer includes endometrial cancer or uterine sarcoma.

116. The method of claim 115, wherein the uterine cancer includes endometrial cancer.

117. The method of claim 116, wherein the endometrial cancer includes endometrial cancer of the uterine body.

118. The method of claim 114, wherein the uterine cancer includes uterine sarcoma.

119. The method of claim 118, wherein the uterine sarcoma includes uterine carcinosarcoma.

120. The method of claim 75, wherein the subject has a midline carcinoma of the NUT.

121. The method of claim 75, wherein the subject has castration-resistant prostate cancer.

122. The method of claim 75, wherein the subject has solid or liquid cancer.

123. The method of claim 75, wherein the subject suffers from a liquid cancer selected from myelofibrosis.

124. The method of claim 75, wherein the subject suffers from a liquid cancer selected from myeloma and leukemia.

125. The method of claim 75, wherein the subject suffers from a liquid cancer selected from leukemia.

126. The method of claim 124, wherein the leukemia is selected from acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

127. The method of claim 75, wherein the loss or absence of function is directed at the EP300 gene.

128. The method according to claim 75 or 76, wherein: R1 is selected from hydrogen; deuterium; -C 1-6 Alkyl group; or -C3-8 carbon ring; and each of which, in each occurrence, is independently and optionally substituted by 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents, in each occurrence, is independently selected from deuterium, halogen, OH, -CN, -C 1-8 Alkyl or -C 1-8 Alkoxy; R2 is selected from hydrogen; deuterium; halogen; -C 1-8 alkyl; Carboxyl group; -COOR 21 ; or -CONR 21 R 22 Each of these elements is independently and optionally substituted by 1, 2, 3, 4, 5, or 6 substituents each time it appears, and each of these substituents is independently selected from deuterium, halogen, -OH, -CN, -NH2, and -C each time it appears. 1-8 Alkyl, -C 1-8 Alkoxy, C 3-8 Carbon rings or six-membered heterocycles containing one, two, or three heteroatoms selected from N or O; R 21 and R 22 Each of these terms is independently selected from hydrogen, deuterium, -OH, NH2, -CN, and -C each time it appears. 1-8 Alkyl; or -C 3-8 Carbon rings; R 23 and R 24 Each of these elements is independently selected from hydrogen, deuterium, or -C each time it appears. 1-8 alkyl; A is selected from or ; Y1 is selected from N or CR Y1 ; Y2 is selected from O, S, and CR. Y1 R Y2 or NR Y2 ; R Y1 and R Y2 Each of these elements is independently selected from hydrogen, deuterium, halogen, -OH, NH2, -CN, -C1-6 alkyl, or -C each time it appears. 1-6 Alkoxy; Each of R3 and R4 is independently selected from hydrogen, deuterium, or -C each time it appears. 1-6 Alkyl groups; and each of them is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents each time it appears, and each of the substituents is independently selected from deuterium, halogen, -OH, -NH2, -CN, -C each time it appears. 1-6 Alkyl or -C 1-6 Alkoxy; n is selected from 0, 1, or 2; W1 is selected from hydrogen; deuterium; -F; -CI; -NH2; -CN; -OH; carboxyl group; -C 1-6 Alkyl; -C 1-6 Alkyl group; a 6-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N and O; wherein each heteroatom is independently and optionally substituted by 1, 2, 3, 4, 5, or 6 substituents each time it appears, and each of the substituents is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, -C 1-3 Alkyl or -C 1-3 Alkoxy; W2 is selected from hydrogen; deuterium; -F; -CI; -NH2; -CN; -OH; carboxyl group; -C 1-3 Alkyl; -C 1-3 Alkoxy; phenyl; naphthyl; a 5-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; a 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; and each of these, in each occurrence, is independently and optionally substituted by 1, 2, 3, 4 or 5 substituents, and each of these substituents, in each occurrence, is selected from deuterium, halogen, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; Z is selected from hydrogen, deuterium, halogen, -NH2, -CN, -OH, or -C. 1-6 Alkyl group.

129. The method according to claim 75 or 76, wherein the compound of formula IV is selected from: (S)-2-(6-(3,5-dimethylisoxazo-4-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; (S)-2-(6-(3,5-dimethylisoxazo-4-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(4,4,4-trifluoro-1-(3-fluoropyridin-2-yl)butyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-((3-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 2-(6-(3,5-dimethylisoxazo-4-yl)-1-methyl-4-((tetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; (S)-2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridine-3-carboxamide; 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)propyl-2-amine; 2-(4-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-6-(1-methyl-4-(methyl-d3)-1H-1,2,3-triazol-5-yl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-fluoropyridin-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((3-methoxypyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)prop-2-ol; and 4-((6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[3,2-b]pyridin-3-yl)methyl)morpholine.

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