Methods of Treating Subjects with Clinically Significant Signs and Symptoms Associated with Blood Cell Differentiation - Patent application

Abstract

Methods are disclosed for treating a subject having clinically significant signs and symptoms associated with blood cell differentiation and being treated with an agent that reduces the level and / or activity of BRG1 and / or BRM. The methods disclosed herein can include, for example, administering to the subject an effective amount of a corticosteroid, hydroxyurea, or furosemide, or subjecting the subject to leukapheresis.

Description

[Background technology]

[0001] Chromatin regulation is essential for gene expression, and ATP-dependent chromatin remodeling is the mechanism by which such gene expression occurs. The human switch / sucrose nonfermenting (SWI / SNF) chromatin remodeling complex, also known as the BAF complex, contains two SWI2-like ATPases, known as BRG1 and BRM. The transcription activator BRG1, also known as the ATP-dependent chromatin remodeling factor SMARCA4, is encoded by the SMARCA4 gene on chromosome 19. BRG1 is overexpressed in several cancer tumors and is required for cancer cell proliferation. BRM, also known as the probable global transcription activator SNF2L2 and / or the ATP-dependent chromatin remodeling factor SMARCA2, is encoded by the SMARCA2 gene on chromosome 9 and has been shown to be essential for tumor cell proliferation in cells characterized by BRG1 loss-of-function mutations. Inactivation of BRG and / or BRM results in downstream effects in cells, including cell cycle arrest and tumor suppression.

[0002] Chromatin regulation is essential for gene expression, and ATP-dependent chromatin remodeling is the mechanism by which such gene expression occurs. The human switch / sucrose nonfermenting (SWI / SNF) chromatin remodeling complex, also known as the BAF complex, contains two SWI2-like ATPases known as BRG1 (Brahma-related gene 1) and BRM (Brahma). The transcription activator BRG1, also known as the ATP-dependent chromatin remodeling factor SMARCA4, is encoded by the SMARCA4 gene on chromosome 19. BRG1 is overexpressed in several cancer tumors and is required for cancer cell proliferation. BRM, also known as the probable global transcription activator SNF2L2 and / or the ATP-dependent chromatin remodeling factor SMARCA2, is encoded by the SMARCA2 gene on chromosome 9 and has been shown to be essential for tumor cell proliferation in cells characterized by BRG1 loss-of-function mutations. Inactivation of BRGs and / or BRMs leads to downstream effects within the cell, including cell cycle arrest and tumor suppression.

[0003] Hematologic cancers, also known as blood cancers, are cancers that begin in blood-forming tissues, such as bone marrow, or in cells of the immune system (e.g., leukemia). Leukemia is a cancer found in the blood and bone marrow and is caused by the rapid production of abnormal white blood cells. In most blood cancers, normal blood cell development is interrupted by uncontrolled growth of abnormal types of blood cells. The abnormal blood cells prevent the blood from performing its many functions. Blood cancers account for approximately 10% of all new cancer diagnoses. The 5-year relative survival rate for blood cancer ranges from approximately 50% to approximately 90%. Summary of the Invention

[0004] The present invention features a method of treating a subject treated with an agent that reduces the level and / or activity of BRG1 and / or BRM. The subject may have clinically significant signs and symptoms associated with blood cell differentiation, may have or be suspected of having a differentiation syndrome, or may have non-infectious leukocytosis. The methods described herein include administering to the subject an effective amount of a corticosteroid, hydroxyurea, or furosemide, or subjecting the subject to leukapheresis.

[0005] In one aspect, the invention provides a method of treating a subject having differentiation syndrome and being treated with an agent that reduces the level and / or activity of BRG1 and / or BRM by administering to the subject an effective amount of a corticosteroid, hydroxyurea, or furosemide, or by subjecting the subject to leukapheresis.

[0006] In another aspect, the invention provides a method of treating a subject suspected of having differentiation syndrome and who has been treated with an agent that reduces the level and / or activity of BRG1 and / or BRM, by administering to the subject an effective amount of a corticosteroid, hydroxyurea, or furosemide, or by subjecting the subject to leukapheresis.

[0007] In some embodiments, the subject is treated with an agent that reduces the level and / or activity of BRG1 and / or BRM in an amount effective for leukemia (e.g., acute myeloid leukemia). In some embodiments, the subject is treated with an agent that reduces the level and / or activity of BRG1 and / or BRM in an amount effective for myelodysplastic syndrome (MDS).

[0008] In some embodiments, the method further comprises administering an agent that reduces the level and / or activity of BRG1 and / or BRM. In yet another aspect, the present invention provides a method of treating a subject having leukemia or myelodysplastic syndrome by administering an effective amount of an agent that reduces the level and / or activity of BRG1 and / or BRM, and, if the subject has clinically significant signs and symptoms associated with blood cell differentiation, administering to the subject an effective amount of a corticosteroid, hydroxyurea, or furosemide, or subjecting the subject to leukapheresis.

[0009] In yet another aspect, the present invention provides a method of treating a subject having leukemia or myelodysplastic syndrome by administering an effective amount of an agent that reduces the level and / or activity of BRG1 and / or BRM, and, if the subject has differentiation syndrome, administering to the subject an effective amount of a corticosteroid, hydroxyurea, or furosemide, or subjecting the subject to leukapheresis.

[0010] In a further aspect, the present invention provides a method of treating a subject having leukemia or myelodysplastic syndrome by administering an effective amount of an agent that reduces the level and / or activity of BRG1 and / or BRM and, if the subject is suspected of having differentiation syndrome, administering to the subject an effective amount of a corticosteroid, hydroxyurea, or furosemide, or subjecting the subject to leukapheresis.

[0011] In some embodiments, the subject has leukemia. In some embodiments, the leukemia is acute myeloid leukemia. In some embodiments, the leukemia is relapsed or refractory acute myeloid leukemia. In some embodiments, the subject has myelodysplastic syndrome.

[0012] In some embodiments, the subject exhibits one or more of the following symptoms: fever of unknown origin, skin rash, hypoxia, respiratory dysfunction, interstitial pulmonary infiltrates, pleural and / or pericardial effusion, weight gain, renal failure, dyspnea, clinical deterioration, fluid in or around the lungs, fluid around the heart, leg swelling, elevated bilirubin, and elevated liver enzymes. In some embodiments, a blood sample from the subject comprises an elevated absolute neutrophil count (ANC) and / or an elevated platelet count.

[0013] In some embodiments, the subject is administered an effective amount of a corticosteroid. In some embodiments, the corticosteroid is administered systemically. In some embodiments, the corticosteroid is administered orally or by injection. In some embodiments, the subject is administered a high dose regimen of a corticosteroid. In some embodiments, the subject is administered a corticosteroid for at least 3 days. In some embodiments, the corticosteroid is dexamethasone, ethamethasoneb, hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, triamcinolone, pharma- ceutically acceptable salts thereof, or combinations thereof. In some embodiments, administration of the agent that reduces the level and / or activity of BRG1 and / or BRM is discontinued if clinically significant signs and symptoms associated with blood cell differentiation or symptoms of differentiation syndrome persist for at least 48 hours after initiation of corticosteroid administration. In some embodiments, administration of the agent that reduces the level and / or activity of BRG1 and / or BRM is discontinued if clinically significant signs and symptoms associated with blood cell differentiation, or symptoms of differentiation syndrome, persist for at least 3 days after initiation of corticosteroid administration.

[0014] In some embodiments, the subject is administered an effective amount of a diuretic. In some embodiments, the diuretic is administered systemically. In some embodiments, the diuretic is administered orally or by injection. In some embodiments, the subject is administered a high dose regimen of a diuretic. In some embodiments, the diuretic is furosemide or a pharma- ceutically acceptable salt thereof.

[0015] In some embodiments, the subject is administered an effective amount of furosemide. In some embodiments, the furosemide is administered systemically. In some embodiments, the furosemide is administered orally or by injection. In some embodiments, the furosemide is administered intramuscularly or intravenously.

[0016] In some embodiments, the subject has symptoms of non-infectious leukocytosis. In some embodiments, the method includes administering an effective amount of hydroxyurea to the subject. In some embodiments, the effective amount of hydroxyurea is administered to the subject until the non-infectious leukocytosis improves or resolves.

[0017] In some embodiments, the method includes subjecting the subject to leukapheresis. In some embodiments, the subject experiences hypervolemia. In some embodiments, an effective amount of furosemide is administered to the subject.

[0018] In some embodiments, the agent that decreases the level and / or activity of BRG1 and / or BRM is a compound of the following structure:

[0019] [ka]

[0020] or a pharma- ceutically acceptable salt thereof. In some embodiments, the agent that decreases the level and / or activity of BRG1 and / or BRM is a compound of the following structure:

[0021] [ka]

[0022] or a pharma- ceutically acceptable salt thereof. In some embodiments, the agent that reduces the level and / or activity of BRG1 and / or BRM is administered orally, hi some embodiments, the agent that reduces the level and / or activity of BRG1 and / or BRM is administered in a unit dosage form selected from the group consisting of a capsule or a tablet.

[0023] In some embodiments of any of the above aspects, an effective amount of the agent reduces the level and / or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance. In some embodiments, an effective amount of the agent reduces the level and / or activity of BRG1 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance. In some embodiments, an effective amount of the agent reduces the level and / or activity of BRG1 by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0024] In some embodiments, an effective amount of an agent reduces BRG1 levels and / or activity by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 ​​hours, 72 hours, or more) compared to a reference substance. In some embodiments, an effective amount of an agent that reduces the level and / or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more) compared to a reference substance.

[0025] In some embodiments of any of the above aspects, an effective amount of the agent reduces the level and / or activity of the BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance. In some embodiments, an effective amount of the agent reduces the level and / or activity of the BRM by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance. In some embodiments, an effective amount of the agent reduces the level and / or activity of the BRM by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0026] In some embodiments, an effective amount of an agent reduces the level and / or activity of a BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 ​​hours, 72 hours, or more) compared to a reference substance. In some embodiments, an effective amount of an agent that reduces the level and / or activity of a BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more) compared to a reference substance.

[0027] In some embodiments, the anti-cancer therapy and the agent that reduces the level and / or activity of BRG1 and / or BRM in a cell are administered within 28 days of each other and each in an amount together effective to treat the subject.

[0028] In some embodiments, the subject or leukemia (e.g., acute myeloid leukemia) has and / or has been identified as having a loss-of-function mutation in BRG1. In some embodiments, the subject or leukemia (e.g., acute myeloid leukemia) has and / or has been identified as having a loss-of-function mutation in BRM. In some embodiments, the leukemia (e.g., acute myeloid leukemia) has a BRG1 T910M mutation.

[0029] In some embodiments, an agent that reduces the level and / or activity of BRG1 and / or BRM in a cell is a small molecule compound, e.g., a small molecule BRG1 and / or BRM inhibitor. In some embodiments, an agent that reduces the level and / or activity of BRG1 and / or BRM in a cell is a small molecule compound, e.g., a small molecule BRG1 inhibitor. In some embodiments, an agent that reduces the level and / or activity of BRG1 and / or BRM in a cell is a small molecule compound, e.g., a small molecule BRM inhibitor or degrader.

[0030] In some embodiments, the small molecule BRG1 and / or BRM inhibitor is a compound having the structure of Formula I, or a pharma- ceutically acceptable salt thereof:

[0031] [ka]

[0032] wherein m is 0, 1, 2, 3, or 4; X 1 is N or CH; Each R 1 are independently selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 It is aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino.

[0033] In some embodiments, the small molecule BRG1 and / or BRM inhibitor is a compound having the structure of Formula II, or a pharma- ceutically acceptable salt thereof:

[0034] [ka]

[0035] In the formula, R 2 is substituted with hydroxy, and optionally independently, halo, cyano, trifluoromethyl, trifluoromethoxy, C 1-3 Alkyl, and C 1-3 phenyl substituted with one or more groups selected from the group consisting of alkoxy; R 3 -R a , -OR a , -N(R a )2, -S(O)2R a and -C(O)-N(R a ) 2 selected from the group consisting of Each R a are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 15-membered carbocyclyl, and 3- to 15-membered heterocyclyl, each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 15-membered carbocyclyl, and 3- to 15-membered heterocyclyl are optionally represented by R b , oxo, halo, -NO2, -N(R b )2, -CN, -C(O)-N(R b )2, -S(O)-N(R b )2, -S(O)2-N(R b )2, -OR b , -SR b , -OC(O)-R b , -C(O)-R b , -C(O)-OR b , -S(O)-R b , -S(O)2-R b , -N(R b )-C(O)-R b , -N(R b )-S(O)-R b , -N(R b )-C(O)-N(R b )2, and -N(R b )-S(O)2-R band is substituted with one or more groups independently selected from the group consisting of: Each R b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 alkoxy, 3- to 15-membered carbocyclyl, and 3- to 15-membered heterocyclyl, each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, 3- to 15-membered carbocyclyl, and 3- to 15-membered heterocyclyl are optionally represented by R c or two R b are optionally substituted, together with the nitrogen to which they are attached, with one or more groups independently selected from the group consisting of oxo and halo, and C 1-3 forming a heterocyclyl optionally substituted with one or more groups independently selected from alkyl; Each R c are independently oxo, halo, -NO2, -N(R d )2, -CN, -C(O)-N(R d )2, -S(O)-N(R d )2, -S(O) 2- N(R d )2, -SR d , -OC(O)-R d , -C(O)-R d , -C(O)-OR d , -S(O)-R d , -S(O) 2- R d , -N(R d )-C(O)-R d , -N(R d )-S(O)-R d , -N(R d )-C(O)-N(R d )2, -N(R d )-S(O) 2- R d , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6alkynyl, 3- to 15-membered carbocyclyl, and 3- to 15-membered heterocyclyl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 15-membered carbocyclyl, and 3- to 15-membered heterocyclyl are R d , oxo, halo, -NO2, -N(R d )2, -CN, -C(O)-N(R d )2, -S(O)-N(R d )2, -S(O)2-N(R d )2, -OR d , -SR d , -OC(O)-R d , -C(O)-R d , -C(O)-R d , -S(O)-R d , -S(O)2-R d , -N(R d )-C(O)-R d , -N(R d )-S(O)-R d , -N(R d )-C(O)-N(R d )2, and -N(R d )-S(O)2-R d and optionally substituted with one or more groups independently selected from the group consisting of Each R d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carbocyclyl, and carbocyclyl (C 1-3 is selected from the group consisting of aryl, arylalkyl, R 4 , H, C 1-6 Alkyl, or -C(=O)-C 1-6 is alkyl, R 5 is H or C 1-6 It is an alkyl.

[0036] Compounds of formula II can be synthesized by methods known in the art, for example, methods described in U.S. Patent Publication No. 2018 / 0086720, the synthetic methods of which are incorporated by reference.

[0037] In some embodiments, the small molecule BRG1 and / or BRM inhibitor is a compound having the structure of formula III, or a pharma- ceutically acceptable salt thereof:

[0038] [ka]

[0039] In the formula, R 6 is halo, e.g., fluoro or chloro; R 7 is hydrogen, an optionally substituted amino, or an optionally substituted C 1-6 is alkyl, R 8 is an arbitrarily substituted C 6-10 Aryl or optionally substituted C 2-9 It is heteroaryl.

[0040] In some embodiments, the small molecule BRG1 and / or BRM inhibitor is a compound having the structure of any one of compounds 1-16, or a pharma- ceutically acceptable salt thereof.

[0041] [ka]

[0042] In some embodiments, the small molecule compound or a pharma- ceutically acceptable salt thereof is a degradant. In some embodiments, the degradant has the structure of formula IV, or a pharma- ceutically acceptable salt thereof: ALB Formula IV wherein A is a binding moiety for BRG1 and / or BRM, L is a linker, and B is a degradation moiety. In some embodiments, the degradation moiety is a ubiquitin ligase moiety. In some embodiments, the ubiquitin ligase binding moiety comprises a cereblon ligand, an IAP (inhibitor of apoptosis) ligand, mouse double minute 2 homolog (MDM2), a hydrophobic tag, or a von Hippel-Lindau ligand, or a derivative or analog thereof.

[0043] In some embodiments, A comprises the structure of any one of formulas I-III, or any one of compounds 1-16. In some embodiments, the hydrophobic tag comprises diphenylmethane, adamantine, or tri-Boc arginine, i.e., the hydrophobic tag comprises the following structure:

[0044] [ka]

[0045] In some embodiments, the ubiquitin ligase binding moiety has the structure of Formula A, or a pharma- ceutically acceptable salt thereof:

[0046] [ka]

[0047] In the formula, X 1 is CH2, O, S, or NR 1 and R 1 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; X 2 is C=O, CH2, or

[0048] [ka]

[0049] and R 3and R 4 is independently H, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl; m is 0, 1, 2, 3, or 4; and each R 2 are independently selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 It is aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino.

[0050] In some embodiments, the ubiquitin ligase binding moiety comprises the structure:

[0051] [ka]

[0052] or a derivative or analog thereof, or a pharma- ceutically acceptable salt thereof. In some embodiments, the ubiquitin ligase binding moiety comprises the structure of Formula B, or a pharma- ceutically acceptable salt thereof:

[0053] [ka]

[0054] In the formula, each R 4 , R 4’ , and R 7 are independently H, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl; R 5 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 aryl, R 6 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 aryl, n is 0, 1, 2, 3, or 4, and each R 8 are independently selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino, and each R 9 and R 10 are independently H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C 10 aryl, R 4’ or R 5 includes a bond to the linker.

[0055] In some embodiments, the ubiquitin ligase binding moiety comprises the structure:

[0056] [ka]

[0057] or a derivative or analog thereof, or a pharma- ceutically acceptable salt thereof. In some embodiments, the ubiquitin ligase binding moiety has the structure of Formula C, or a pharma- ceutically acceptable salt thereof:

[0058] [ka]

[0059] In the formula, each R 11 , R 13 , and R 15 are independently H, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl; R 12 is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 aryl, R 14 is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 aryl, p is 0, 1, 2, 3, or 4, and each R 16 are independently selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; q is 0, 1, 2, 3, or 4; and each R 17 are independently selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 It is aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino.

[0060] In some embodiments, the ubiquitin ligase binding moiety comprises the structure:

[0061] [ka]

[0062] or a derivative or analog thereof, or a pharma- ceutically acceptable salt thereof. In some embodiments, the ubiquitin ligase binding moiety has the structure of Formula D, or a pharma- ceutically acceptable salt thereof:

[0063] [ka]

[0064] In the formula, each R 18 and R 19 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 aryl, r1 is 0, 1, 2, 3, or 4, and each R 20 are independently selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; r2 is 0, 1, 2, 3, or 4; and each R 21 are independently selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 It is aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino.

[0065] In some embodiments, the ubiquitin ligase binding moiety comprises the structure:

[0066] [ka]

[0067] or a derivative or analog thereof, or a pharma- ceutically acceptable salt thereof. In some embodiments, the linker has the structure of Formula V: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D)-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 Formula V In the formula, A 1 is the bond between the linker and A, A 2 is the bond between B and the linker, and B 1 , B 2 , B3 , and B 4 are each independently an optionally substituted C1-C2 alkyl, an optionally substituted C1-C3 heteroalkyl, O, S, S(O) 2、 and N.R. N Selected from R N is hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 2-6 Heterocyclyl, optionally substituted C 6-12 Aryl, or optionally substituted C 1-7 Heteroalkyl, C 1 and C 2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, I, j, and k are each independently 0 or 1; D is an optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, optionally substituted C 2-10 Alkynyl, optionally substituted C 2-6 Heterocyclyl, optionally substituted C 6-12 Aryl, optionally substituted C2-C 10 Polyethylene glycol, or any substituted C 1-10 Heteroalkyl, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 is a chemical bond that connects

[0068] In some embodiments, D is an optionally substituted C-C 10 In some embodiments, C is polyethylene glycol. 1 and C 2Each is independently carbonyl or sulfonyl. In some embodiments, B 1 , B 2 , B 3 , and B 4 are each independently an optionally substituted C1-C2 alkyl, an optionally substituted C1-C3 heteroalkyl, O, S, S(O)2, and NR N Selected from R N is hydrogen or an optionally substituted C 1-4 In some embodiments, B is alkyl. 1 , B 2 , B 3 , and B 4 are each independently selected from optionally substituted C1-C2 alkyl or optionally substituted C1-C3 heteroalkyl. In some embodiments, j is 0. In some embodiments, k is 0. In some embodiments, j and k are each independently 0. In some embodiments, f, g, h, and i are each independently 1.

[0069] In some embodiments, the linker of formula V has the structure of formula Va:

[0070] [ka]

[0071] In the formula, A 1 is the bond between the linker and A, and A 2 is the bond between B and the linker. In some embodiments, D is optionally substituted C 1-10 In some embodiments, C 1 and C 2 Each is independently carbonyl. In some embodiments, B 1 , B 2 , B 3 , and B 4 are each independently an optionally substituted C1-C2 alkyl, an optionally substituted C1-C3 heteroalkyl, O, S, S(O)2, and NR NSelected from R N is hydrogen or an optionally substituted C 1-4 In some embodiments, B is alkyl. 1 , B 2 , B 3 , and B 4 each independently represents an optionally substituted C1-C2 alkyl, O, S, S(O)2, and NR N Selected from R N is hydrogen or an optionally substituted C 1-4 In some embodiments, B is alkyl. 1 and B. 4 Each independently is an optionally substituted C1-C2 alkyl. In some embodiments, B 1 and B. 4 Each is independently C alkyl. In some embodiments, B 2 and B. 4 are each independently NR N and R N is hydrogen or an optionally substituted C 1-4 In some embodiments, B is alkyl. 2 and B. 4 In some embodiments, f, g, h, I, j, and k are each independently 1.

[0072] In some embodiments, the linker of formula V has the structure of formula Vb:

[0073] [ka]

[0074] In the formula, A 1 is the bond between the linker and A, and A 2 is the bond between B and the linker. In some embodiments, the leukemia (e.g., acute myeloid leukemia) is resistant to one or more chemotherapeutic or cytotoxic agents (e.g., the leukemia (e.g., acute myeloid leukemia) has been determined, such as by genetic markers, to be resistant to a chemotherapeutic or cytotoxic agent or has been determined to be likely to be resistant to a chemotherapeutic or cytotoxic agent, such as a leukemia (e.g., acute myeloid leukemia) that has failed to respond to a chemotherapeutic or cytotoxic agent). In some embodiments, the leukemia (e.g., acute myeloid leukemia) has failed to respond to one or more chemotherapeutic or cytotoxic agents. In some embodiments, the leukemia (e.g., acute myeloid leukemia) is resistant to or has failed to respond to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, CTLA-4 inhibitors (e.g., ipilimumab), PD-1 inhibitors (e.g., nivolumab or pembrolizumab), PD-L1 inhibitors (e.g., atezolizumab, avelumab, or durvalumab), mitogen-activated protein kinase (MEK) inhibitors (e.g., selumetinib, binimetinib, or trametinib), and / or protein kinase C (PKC) inhibitors (e.g., sotrastaurin or LXS196, also known as IDE196).

[0075] In some embodiments, the leukemia (e.g., acute myeloid leukemia) is resistant to or has failed to respond to previously administered therapeutic agents used to treat uveal melanoma, such as MEK inhibitors or PKC inhibitors. For example, in some embodiments, the leukemia (e.g., acute myeloid leukemia) is resistant to or has failed to respond to mitogen-activated protein kinase (MEK) inhibitors (e.g., selumetinib, binimetinib, or trametinib) and / or protein kinase C (PKC) inhibitors (e.g., sotrastaurin or LXS196).

[0076] In some embodiments, the agent that reduces the level and / or activity of BRG1 and / or BRM in a cell is a small molecule compound, an antibody, an enzyme, and / or a polynucleotide.

[0077] In some embodiments, the agent that reduces the level and / or activity of BRG1 and / or BRM in a cell is an enzyme, e.g., a clustered regularly interspaced short palindromic repeats (CRISPR) associated protein, e.g., CRISPR-associated protein 9 (Cas9), CRISPR-associated protein 12a (Cas12a), a zinc finger nuclease (ZFN), a transcription activator-like effector nuclease (TALEN), or a meganuclease.

[0078] In some embodiments, the agent that reduces the level and / or activity of BRG1 and / or BRM in a cell is a polynucleotide, e.g., an antisense nucleic acid, a small interfering RNA (siRNA), a small hairpin RNA (shRNA), a microRNA (miRNA), a CRISPR / Cas9 nucleotide, or a ribozyme.

[0079] In some embodiments, the leukemia is acute myeloid leukemia. In some embodiments, the leukemia is advanced. chemical terms For any of the following chemical definitions, the number following the atomic symbol indicates the total number of atoms of that element present in a particular chemical moiety. As will be understood, other atoms such as hydrogen atoms or substituents as described herein may be present to satisfy the valence of the atom, if necessary. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. When used with groups defined herein, references to the number of carbon atoms include the divalent carbons in acetal and ketal groups, but do not include the carbonyl carbons in acyl, ester, carbonate, or carbamate groups. References to the number of oxygen, nitrogen, or sulfur atoms in heteroaryl groups include only those atoms that form part of the heterocyclic ring.

[0080] The term "acyl," as used herein, refers to a hydrogen or alkyl group, as defined herein, attached to the parent molecular group through a carbonyl group, and is exemplified by formyl (i.e., a carboxaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups contain 1 to 6, 1 to 11, or 1 to 21 carbons.

[0081] The term "alkyl," as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms).

[0082] Alkylene is a divalent alkyl group. As used herein, the term "alkenyl," alone or in combination with other groups, refers to a straight-chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

[0083] As used herein, the term "alkynyl," alone or in combination with other groups, refers to a straight-chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

[0084] As used herein, the term “amino” refers to —N(R N1 )2, wherein each R N1 are independently H, OH, NO2, N(R N2 )2, SO2OR N2 , SO2R N2 , SOR N2 , an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), and these indicated R N1Each of the groups may be optionally substituted or may have two R N1 are taken together to form an alkylene or heteroalkylene, and each R N2 is independently H, alkyl, or aryl. The amino group of the compounds described herein may be unsubstituted amino (i.e., -NH) or substituted amino (i.e., -N(R N1 )2).

[0085] As used herein, the term "aryl" refers to a carbomonocyclic or carbopolycyclic aromatic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.

[0086] As used herein, the term "arylalkyl" refers to an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are 7-30 carbon (e.g., C1-C6 alkyl, C6 ... 10 Aryl, C1-C 10 Alkyl C6-C 10 Aryl, or C1-C 20 Alkyl C6-C 10 aryl, 7-16 or 7-20 carbons, etc. In some embodiments, alkyl and aryl can each be further substituted with 1, 2, 3, or 4 substituents (defined herein) for each group.

[0087] As used herein, the term "azido" refers to a -N3 group. As used herein, the term "bridged polycycloalkyl" refers to a bridged polycyclic group of 5 to 20 carbons containing 1 to 3 bridges.

[0088] As used herein, the term "cyano" refers to a -CN group. As used herein, the term "carbocyclyl" refers to a non-aromatic C-C ring formed by carbon atoms. 12 It refers to a monocyclic, bicyclic, or tricyclic structure. The carbocyclyl structure includes a cycloalkyl group and an unsaturated carbocyclyl radical.

[0089] As used herein, the term "cycloalkyl" refers to a saturated non-aromatic monovalent mono- or polycarbocyclic radical of three to ten, preferably three to six, carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

[0090] As used herein, the term "halogen" means a radical of fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo). As used herein, the term "heteroalkyl" refers to an alkyl group (as defined herein) in which one or more of the constituent carbon atoms are replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group may be further substituted with one, two, three, or four substituents as set forth herein for alkyl groups. An example of a heteroalkyl group is "alkoxy," which as used herein refers to alkyl-O- (e.g., methoxy and ethoxy). Heteroalkylene is a divalent heteroalkyl group. As used herein, the term "heteroalkenyl" refers to an alkenyl group (as defined herein) in which one or more of the constituent carbon atoms are replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group may be further substituted with one, two, three, or four substituents as set forth herein for alkenyl groups. An example of a heteroalkenyl group is "alkenoxy," which as used herein refers to alkenyl-O-. Heteroalkenylene is a divalent heteroalkenyl group. The term "heteroalkynyl" as used herein refers to an alkynyl group (as defined herein) in which one or more of the constituent carbon atoms is replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group may be further substituted with one, two, three, or four substituents as indicated herein for alkynyl groups. An example of a heteroalkynyl group is "alkynoxy", which as used herein refers to alkynyl-O-. Heteroalkynylene is a divalent heteroalkynyl group.

[0091] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic radical of 5 to 12 atoms having at least one aromatic ring and containing 1, 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced by a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.

[0092] As used herein, the term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups include those having 7 to 30 carbons (e.g., C1-C6 alkyl, C2-C9 heteroaryl, C1-C 10 Alkyl C2-C9 Heteroaryl, or C1-C 20 and 7-16 or 7-20 carbons, such as alkyl C2-C9 heteroaryl. In some embodiments, alkyl and heteroaryl can each be further substituted with 1, 2, 3, or 4 substituents, as indicated herein for each group.

[0093] As used herein, the term "heterocyclyl" refers to a monocyclic or polycyclic radical having 3 to 12 atoms with at least one ring containing 1, 2, 3, or 4 ring atoms selected from N, O, or S, and the ring is not aromatic. Examples of heterocyclyl include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl.

[0094] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups include those having 7 to 30 carbons (e.g., C1-C6 alkyl, C2-C9 heterocyclyl, C1-C 10 Alkyl C2-C9 heterocyclyl, or C1-C 20 and 7-16 or 7-20 carbons, such as alkyl C2-C9 heterocyclyl. In some embodiments, alkyl and heterocyclyl can each be further substituted with 1, 2, 3, or 4 substituents, as defined herein for each group.

[0095] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with an --OH group. As used herein, the term "hydroxyl" refers to an --OH group.

[0096] As used herein, the term "N-protecting group" refers to a group intended to protect an amino group against undesired reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 3rd Edition (John Wiley & Sons, New York, 1999).N-protecting groups include acyl, aryl, and the like, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries, such as protected or unprotected D,L, or D,L-amino acids, such as alanine, leucine, and phenylalanine. p-nitrobenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-20-dimethoxybenzyloxycarbonyl, 4-Methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl 3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl Examples of N-protecting groups include, but are not limited to, carbamate-forming groups such as aryl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and silyl groups such as trimethylsilyl. Preferred N-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0097] As used herein, the term "nitro" refers to a -NO2 group. As used herein, the term "thiol" refers to a --SH group. The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. If substituted, typically 1 to 4 substituents may be present unless otherwise specified. Substituents include, for example, alkyl (e.g., unsubstituted and substituted, where the substituents include any of the groups described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkylamino), azido, cyano, nitro, or thiol. The aryl, carbocyclyl (eg, cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted, for example, arylalkyl (eg, substituted and unsubstituted benzyl)).

[0098] The compounds described herein may have one or more asymmetric carbon atoms and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, or mixtures of diastereoisomeric racemates. Optically active forms can be obtained, for example, by resolution of racemates, by asymmetric synthesis or asymmetric chromatography (chromatography using chiral adsorbents or eluents). That is, certain disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are most commonly pairs of stereoisomers whose mirror images are not superimposable because they contain asymmetrically substituted carbon atoms that function as chiral centers. Enantiomers refer to one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating the enantiomers from the racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. Suitable techniques and / or methods for separating the enantiomers of the compounds described herein from racemic mixtures can be readily determined by one of ordinary skill in the art. "Racemate" or "racemic mixture" refers to a compound containing two enantiomers, and such mixtures do not exhibit optical activity, i.e., they do not rotate the plane of polarized light. "Geometric isomer" refers to isomers that differ in the orientation of the substituent atoms in relation to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. The atoms (other than H) on each side of the carbon-carbon double bond can be in the E (substituents are on the 25 opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. "R", "S", "S*", "R*", "E", "Z", "cis", and "trans" indicate the configurations relative to the core molecule.Certain disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation around a single bond, where the steric strain barrier to rotation is high enough to allow isolation of the conformers. The compounds described herein may be prepared as individual isomers by isomer-specific synthesis or resolved from an isomeric mixture. Traditional resolution techniques include forming a salt of the free base of each isomer of the isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming a salt of the acid form of each isomer of the isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide 35 of each of the isomers of the isomeric pair using an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving the isomeric mixture of either the starting material or the final product using a variety of well-known chromatographic methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure relative to the other stereoisomer. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure. Percent optical purity is the weight of the enantiomer, or the ratio of the weight of the enantiomer to the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer to the weight of all diastereomers. When the stereochemistry of a disclosed compound is named or shown by structure, the named or shown stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction relative to the other stereoisomer.When a single enantiomer is named or shown by structure, the shown or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction. When a single diastereomer is named or shown by structure, the shown or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction. Percent purity by mole fraction is the ratio of moles of enantiomer, or moles of enantiomer and moles of its optical isomer. Similarly, percent purity by mole fraction is the ratio of moles of diastereomer, or moles of diastereomer and moles of its isomer. When a disclosed compound is named or shown by structure without showing stereochemistry and the compound has at least one chiral center, the name or structure should be understood to encompass any of the enantiomers of the compound without the corresponding optical isomer, a racemic mixture of the compound, a mixture of the compound, or a mixture enriched in one enantiomer with respect to its corresponding optical isomer. When a disclosed compound is named or shown by structure without showing stereochemistry and has two or more chiral centers, the name or structure should be understood to encompass any of the diastereomers without the other diastereomers, some diastereomers without other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers enriched in one diastereomer with respect to other diastereomer(s), or mixtures of diastereomers enriched in one or more diastereomers with respect to other diastereomers. The present invention encompasses all of these forms.

[0099] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Methods and materials for use in this disclosure are described herein. Other suitable methods and materials known in the art may also be used. Materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0100] definition In this application, unless otherwise clear from the context, (i) the term "a" may be understood to mean "at least one," (ii) the term "or" may be understood to mean "and / or," and (iii) the terms "comprising" and "including" may be understood to encompass the individual elements or steps, whether presented alone or together with one or more additional elements or steps.

[0101] As used herein, the terms "about" and "approximately" refer to values ​​within 10% above or below the stated value. For example, the term "about 5%" indicates a range of 4.5 to 5.5%.

[0102] As used herein, the term "administration" refers to administration of a composition (e.g., a compound or preparation including a compound described herein) to a subject or system. Administration to an animal subject (e.g., to a human) can be by any suitable route. For example, in some embodiments, administration can be bronchial (including by bronchial instillation), buccal, enteral, intradermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, intravaginal, and intravitreal.

[0103] As used herein, the term "BAF complex" refers to a complex of BRG1- or HBRM-associated factors in human cells. As used herein, the term "BAF complex-associated disorder" refers to a disorder that is caused by or affected by the level of activity of the BAF complex.

[0104] As used herein, the term "BRG1" refers to the ATP-dependent chromatin remodeler SMARCA4. BRG1 is a component of the BAF complex, the SWI / SNF ATPase chromatin remodeling complex. Human BRG1 is encoded by the SMARCA4 gene on chromosome 19, the nucleic acid sequence of which is shown in SEQ ID NO: 1 (GenBank accession number NM_001128849.1 (mRNA), www.ncbi.nlm.nih.gov / nuccore / NM_001128849.1?report=fasta). GGCGGGGGAGGCGCCGGGAAGTCGACGGCGCCGGCGGCTCCTGCAGGAGGCCACTGTCTGCAGCTCCCGT GAAGATGTCCACTCCAGACCCACCCCTGGGCGGAACTCCTCGGCCAGGTCCTTCCCCGGGCCCTGGCCCT TCCCCTGGAGCCATGCTGGGCCCTAGCCCGGGTCCCTCGCCGGGCTCCGCCCACAGCATGATGGGGCCCA GCCCAGGGCCGCCCTCAGCAGGACACCCCATCCCCACCCAGGGGCCTGGAGGGTACCCTCAGGACAACAT GCACCAGATGCACAAGCCCATGGAGTCCATGCATGAGAAGGGCATGTCGGACGACCCGCGCTACAACCAG ATGAAAGGAATGGGGATGCGGTCAGGGGGCCATGCTGGGATGGGGCCCCCGCCCAGCCCCATGGACCAGC ACTCCCAAGGTTACCCCTCGCCCCTGGGTGGCTCTGAGCATGCCTCTAGTCCAGTTCCAGCCAGTGGCCC GTCTTCGGGGCCCCAGATGTCTTCCGGGCCAGGAGGTGCCCCGCTGGATGGTGCTGACCCCCAGGCCTTG GGGCAGCAGAACCGGGGCCCAACCCCATTTAACCAGAACCAGCTGCACCAGCTCAGAGCTCAGATCATGG CCTACAAGATGCTGGCCAGGGGGCAGCCCCTCCCCGACCACCTGCAGATGGCGGTGCAGGGCAAGCGGCC GATGCCCGGGATGCAGCAGCAGATGCCAACGCTACCTCCACCCTCGGTGTCCGCAACAGGACCCGGCCCT GGCCCTGGCCCTGGCCCCGGCCCGGGTCCCGGCCCGGCACCTCCAAATTACAGCAGGCCTCATGGTATGG GAGGGCCCAACATGCCTCCCCCAGGACCCTCGGGCGTGCCCCCCGGGATGCCAGGCCAGCCTCCTGGAGG GCCTCCCAAGCCCTGGCCTGAAGGACCCATGGCGAATGCTGCTGCCCCCACGAGCACCCCTCAGAAGCTG ATTCCCCCGCAGCCAACGGGCCGCCCTTCCCCCGCGCCCCCTGCCGTCCCACCCGCCGCCTCGCCCGTGA TGCCACCGCAGACCCAGTCCCCCGGGCAGCCGGCCCAGCCCGCGCCCATGGTGCCACTGCACCAGAAGCA GAGCCGCATCACCCCCATCCAGAAGCCGCGGGGCCTCGACCCTGTGGAGATCCTGCAGGAGCGCGAGTAC AGGCTGCAGGCTCGCATCGCACACCGAATTCAGGAACTTGAAAACCTTCCCGGGTCCCTGGCCGGGGATT TGCGAACCAAAGCGACCATTGAGCTCAAGGCCCTCAGGCTGCTGAACTTCCAGAGGCAGCTGCGCCAGGA GGTGGTGGTGTGCATGCGGAGGGACACAGCGCTGGAGACAGCCCTCAATGCTAAGGCCTACAAGCGCAGC AAGCGCCAGTCCCTGCGCGAGGCCCGCATCACTGAGAAGCTGGAGAAGCAGCAGAAGATCGAGCAGGAGC GCAAGCGCCGGCAGAAGCACCAGGAATACCTCAATAGCATTCTCCAGCATGCCAAGGATTTCAAGGAATA TCACAGATCCGTCACAGGCAAAATCCAGAAGCTGACCAAGGCAGTGGCCACGTACCATGCCAACACGGAG CGGGAGCAGAAGAAAGAGAACGAGCGGATCGAGAAGGAGCGCATGCGGAGGCTCATGGCTGAAGATGAGG AGGGGTACCGCAAGCTCATCGACCAGAAGAAGGACAAGCGCCTGGCCTACCTCTTGCAGCAGACAGACGA GTACGTGGCTAACCTCACGGAGCTGGTGCGGCAGCACAAGGCTGCCCAGGTCGCCAAGGAGAAAAAGAAG AAAAAGAAAAAGAAGAAGGCAGAAAATGCAGAAGGACAGACGCCTGCCATTGGGCCGGATGGCGAGCCTC TGGACGAGACCAGCCAGATGAGCGACCTCCCGGTGAAGGTGATCCACGTGGAGAGTGGGAAGATCCTCAC AGGCACAGATGCCCCCAAAGCCGGGCAGCTGGAGGCCTGGCTCGAGATGAACCCGGGGTATGAAGTAGCT CCGAGGTCTGATAGTGAAGAAAGTGGCTCAGAAGAAGAGGAAGAGGAGGAGGAGGAAGAGCAGCCGCAGG CAGCACAGCCTCCCACCCTGCCCGTGGAGGAGAAGAAGAAGATTCCAGATCCAGACAGCGATGACGTCTC TGAGGTGGACGCGCGGCACATCATTGAGAATGCCAAGCAAGATGTCGATGATGAATATGGCGTGTCCCAG GCCCTTGCACGTGGCCTGCAGTCCTACTATGCCGTGGCCCATGCTGTCACTGAGAGAGTGGACAAGCAGT CAGCGCTTATGGTCAATGGTGTCCTCAAACAGTACCAGATCAAAGGTTTGGAGTGGCTGGTGTCCCTGTA CAACAACAACCTGAACGGCATCCTGGCCGACGAGATGGGCCTGGGGAAGACCATCCAGACCATCGCGCTC ATCACGTACCTCATGGAGCACAAACGCATCAATGGGCCCTTCCTCATCATCGTGCCTCTCTCAACGCTGT CCAACTGGGCGTACGAGTTTGACAAGTGGGCCCCCTCCGTGGTGAAGGTGTCTTACAAGGGATCCCCAGC AGCAAGACGGGCCTTTGTCCCCCAGCTCCGGAGTGGGAAGTTCAACGTCTTGCTGACGACGTACGAGTAC ATCATCAAAGACAAGCACATCCTCGCCAAGATCCGTTGGAAGTACATGATTGTGGACGAAGGTCACCGCA TGAAGAACCACCACTGCAAGCTGACGCAGGTGCTCAACACGCACTATGTGGCACCCCGCCGCCTGCTGCT GACGGGCACACCGCTGCAGAACAAGCTTCCCGAGCTCTGGGCGCTGCTCAACTTCCTGCTGCCCACCATC TTCAAGAGCTGCAGCACCTTCGAGCAGTGGTTTAACGCACCCTTTGCCATGACCGGGGAAAAGGTGGACC TGAATGAGGAGGAAACCATTCTCATCATCCGGCGTCTCCACAAAGTGCTGCGGCCCTTCTTGCTCCGACG ACTCAAGAAGGAAGTCGAGGCCCAGTTGCCCGAAAAGGTGGAGTACGTCATCAAGTGCGACATGTCTGCG CTGCAGCGAGTGCTCTACCGCCACATGCAGGCCAAGGGCGTGCTGCTGACTGATGGCTCCGAGAAGGACA AGAAGGGCAAAGGCGGCACCAAGACCCTGATGAACACCATCATGCAGCTGCGGAAGATCTGCAACCACCC CTACATGTTCCAGCACATCGAGGAGTCCTTTTCCGAGCACTTGGGGTTCACTGGCGGCATTGTCCAAGGG CTGGACCTGTACCGAGCCTCGGGTAAATTTGAGCTTCTTGATAGAATTCTTCCCAAACTCCGAGCAACCA ACCACAAAGTGCTGCTGTTCTGCCAAATGACCTCCCTCATGACCATCATGGAAGATTACTTTGCGTATCG CGGCTTTAAATACCTCAGGCTTGATGGAACCACGAAGGCGGAGGACCGGGGCATGCTGCTGAAAACCTTC AACGAGCCCGGCTCTGAGTACTTCATCTTCCTGCTCAGCACCCGGGCTGGGGGGCTCGGCCTGAACCTCC AGTCGGCAGACACTGTGATCATTTTTGACAGCGACTGGAATCCTCACCAGGACCTGCAAGCGCAGGACCG AGCCCACCGCATCGGGCAGCAGAACGAGGTGCGTGTGCTCCGCCTCTGCACCGTCAACAGCGTGGAGGAG AAGATCCTAGCTGCAGCCAAGTACAAGCTCAACGTGGACCAGAAGGTGATCCAGGCCGGCATGTTCGACC AGAAGTCCTCCAGCCATGAGCGGCGCGCCTTCCTGCAGGCCATCCTGGAGCACGAGGAGCAGGATGAGAG CAGACACTGCAGCACGGGCAGCGGCAGTGCCAGCTTCGCCCACACTGCCCCTCCGCCAGCGGGCGTCAAC CCCGACTTGGAGGAGCCACCTCTAAAGGAGGAAGACGAGGTGCCCGACGACGAGACCGTCAACCAGATGA TCGCCCGGCACGAGGAGGAGTTTGATCTGTTCATGCGCATGGACCTGGACCGCAGGCGCGAGGAGGCCCG CAACCCCAAGCGGAAGCCGCGCCTCATGGAGGAGGACGAGCTCCCCTCGTGGATCATCAAGGACGACGCG GAGGTGGAGCGGCTGACCTGTGAGGAGGAGGAGGAGAAGATGTTCGGCCGTGGCTCCCGCCACCGCAAGG AGGTGGACTACAGCGACTCACTGACGGAGAAGCAGTGGCTCAAGAAAATTACAGGAAAAGATATCCATGA CACAGCCAGCAGTGTGGCACGTGGGCTACAATTCCAGCGTGGCCTTCAGTTCTGCACACGTGCGTCAAAG GCCATCGAGGAGGGCACGCTGGAGGAGATCGAAGAGGAGGTCCGGCAGAAGAAATCATCACGGAAGCGCA AGCGAGACAGCGACGCCGGCTCCTCCACCCCGACCACCAGCACCCGCAGCCGCGACAAGGACGACGAGAG CAAGAAGCAGAAGAAGCGCGGGCGGCCGCCTGCCGAGAAACTCTCCCCTAACCCACCCAACCTCACCAAG AAGATGAAGAAGATTGTGGATGCCGTGATCAAGTACAAGGACAGCAGCAGTGGACGTCAGCTCAGCGAGG TCTTCATCCAGCTGCCCTCGCGAAAGGAGCTGCCCGAGTACTACGAGCTCATCCGCAAGCCCGTGGACTT CAAGAAGATAAAGGAGCGCATTCGCAACCACAAGTACCGCAGCCTCAACGACCTAGAGAAGGACGTCATG CTCCTGTGCCAGAACGCACAGACCTTCAACCTGGAGGGCTCCCTGATCTATGAAGACTCCATCGTCTTGC AGTCGGTCTTCACCAGCGTGCGGCAGAAATCGAGAAGGAGGATGACAGTGAAGGCGAGGAGAGTGAG GGAGGAAGAGGCGAGGAGGAAGGCTCCGAATCCGAATCTCGGTCCGTCAAAGTGAAGATCAAGCTTGGC CGGAAGGAGAAGGCACAGGACCGGCTGAAGGGCGGCCGGCGGCGGCCGAGCCGAGGGTCCCGAGCCAAGC CGGTCGTGAGTGACGATGACAGTGAGGAGGAAACAAGAGGAGGACCGCTCAGGAAGTGGCAGCGAAGAAGA CTGAGCCCGACATTCCAGTCTCGACCCCGAGCCCCTCGTTCCAGAGCTGAGATGGCATAGGCCTTAGCA GTAACGGGTAGCAGCAGATGTAGTTTCAGACTTGGAGTAAAACTGTATAAACAAAAGAATCTTCCATATT TATACAGCAGAGAAGCTGTAGGACTGTTTGTGACTGGCCCTGTCCTGGCATCAGTAGCATCTGTAACAGC ATTAACTGTCTTAAAGAGAGAGAGAGAGAATTCCGAATTGGGGAACACACGATACCTGTTTTTCTTTTCC GTTGCTGGCAGTACTGTTGCGCCGCAGTTTGGAGTCACTGTAGTTAAGTGTGGATGCATGTGCGTCACCG TCCACTCCTCCTACTGTATTTTATTGGACAGGTCAGACTCGCCGGGGCCCGGCGAGGGTATGTCAGTGT CACTGGATGTCAAACAGTAATAAATTAAACCAACAACAAAACGCACAGCCAAAAAAAAA The term "BRG1" also refers to naturally occurring variants of wild-type human BRG1 protein, such as proteins having at least 85% identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity or more) to the amino acid sequence of wild-type BRG1 set forth in SEQ ID NO:2 (UniProt Accession No. P51532, www.uniprot.org / uniprot / P51532.fasta).

[0105] SEQ ID NO:2. MSTPDPPLGGTPRPGPSPGPGPSPGAMLGPSPGPSPGSAHSMMGPSPGPPSAGHPIPTQG PGGYPQDNMHQMHKPMESMHEKGMSDDPRYNQMKGMGMRSGGHAGMGPPPSPMDQHSQGY PSPLGGSEHASSPVPASGPSSGPQMSSGPGGAPLDGADPQALGQQNRGPTPFNQNQLHQL RAQIMAYKMLARGQPLPDHLQMAVQGKRPMPGMQQQMPTLPPPSVSATGPGPGPGPGPGP GPGPAPPNYSRPHGMGGPNMPPPGPSGVPPGMPGQPPGGPPKPWPEGPMANAAAPTSTPQ KLIPPQPTGRPSPAPPAVPPAASPVMPPQTQSPGQPAQPAPMVPLHQKQSRITPIQKPRG LDPVEILQEREYRLQARIAHRIQELENLPGSLAGDLRTKATIELKALRLLNFQRQLRQEV VVCMRRDTALETALNAKAYKRSKRQSLREARITEKLEKQQKIEQERKRRQKHQEYLNSIL QHAKDFKEYHRSVTGKIQKLTKAVATYHANTEREQKKENERIEKERMRRLMAEDEEGYRK LIDQKKDKRLAYLLQQTDEYVANLTELVRQHKAAQVAKEKKKKKKKKKAENAEGQTPAIG PDGEPLDETSQMSDLPVKVIHVESGKILTGTDAPKAGQLEAWLEMNPGYEVAPRSDSEES GSEEEEEEEEEEQPQAAQPPTLPVEEKKKIPDPDSDDVSEVDARHIIENAKQDVDDEYGV SQALARGLQSYYAVAHAVTERVDKQSALMVNGVLKQYQIKGLEWLVSLYNNNLNGILADE MGLGKTIQTIALITYLMEHKRINGPFLIIVPLSTLSNWAYEFDKWAPSVVKVSYKGSPAA RRAFVPQLRSGKFNVLLTTYEYIIKDKHILAKIRWKYMIVDEGHRMKNHHCKLTQVLNTH YVAPRRLLLTGTPLQNKLPELWALLNFLLPTIFKSCSTFEQWFNAPFAMTGEKVDLNEEE TILIIRRLHKVLRPFLLRRLKKEVEAQLPEKVEYVIKCDMSALQRVLYRHMQAKGVLLTD GSEKDKKGKGGTKTLMNTIMQLRKICNHPYMFQHIEESFSEHLGFTGGIVQGLDLYRASG KFELLDRILPKLRATNHKVLLFCQMTSLMTIMEDYFAYRGFKYLRLDGTTKAEDRGMLLK TFNEPGSEYFIFLLSTRAGGLGLNLQSADTVIIFDSDWNPHQDLQAQDRAHRIGQQNEVR VLRLCTVNSVEEKILAAAKYKLNVDQKVIQAGMFDQKSSSHERRAFLQAILEHEEQDESR HCSTGSGSASFAHTAPPPAGVNPDLEEPPLKEEDEVPDDETVNQMIARHEEEFDLFMRMD LDRRREEEARNPKRKPRLMEEDELPSWIIKDDAEVERLTCEEEEEKMFGRGSRHRKEVDYS DSLTEKQWLKAIEEGTLEEIEEEVRQKKSSRKRKRDSDAGSSTPTTSTRSRDKDDESKKQ KKRGRPPAEKLSPNPPNLTKKMKKIVDAVIKYKDSSSGRQLSEVFIQLPSRKELPEYYEL IRKPVDFKKIKERIRNHKYRSLNDLEKDVMLLCQNAQTFNLEGSLIYEDSIVLQSVFTSV RQKIEKEDDSEGEESEEEEEGEEEGSESESRSVKVKIKLGRKEKAQDRLKGGRRRPSRGS RAKPVVSDDDSEEEQEEDRSGSGSEED As used herein, the term "BRM" refers to the potential global transcriptional activator SNF2L2. BRM is a component of the BAF complex, the SWI / SNF ATPase chromatin remodeling complex. Human BRM is encoded by the SMARCA2 gene on chromosome 9, the nucleic acid sequence of which is shown in SEQ ID NO: 3 (GenBank Accession No. NM_003070.4 www.ncbi.nlm.nih.gov / nuccore / NM_003070.4?report=fasta).

[0106] SEQ ID NO:3. GCGTCTTCCGGCGCCCGCGGAGGAGGCGAGGGTGGGACGCTGGGCGGAGCCCGAGTTTAGGAAGAGGAGG GGACGGCTGTCATCAATGAAGTCATATTCATAATCTAGTCCTCTCTCCCTCTGTTTCTGTACTCTGGGTG ACTCAGAGAGGGAAGAGATTCAGCCAGCACACTCCTCGCGAGCAAGCATTACTCTACTGACTGGCAGAGA CAGGAGAGGTAGATGTCCACGCCCACAGACCCTGGTGCGATGCCCCACCCAGGGCCTTCGCCGGGGCCTG GGCCTTCCCCTGGGCCAATTCTTGGGCCTAGTCCAGGACCAGGACCATCCCCAGGTTCCGTCCACAGCAT GATGGGGCCAAGTCCTGGACCTCCAAGTGTCTCCCATCCTATGCCGACGATGGGGTCCACAGACTTCCCA CAGGAAGGCATGCATCAAATGCATAAGCCCATCGATGGTATACATGACAAGGGGATTGTAGAAGACATCC ATTGTGGATCCATGAAGGGCACTGGTATGCGACCACCTCACCCAGGCATGGGCCCTCCCCAGAGTCCAAT GGATCAACACAGCCAAGGTTATATGTCACCACACCCATCTCCATTAGGAGCCCCAGAGCACGTCTCCAGC CCTATGTCTGGAGGAGGCCCAACTCCACCTCAGATGCCACCAAGCCAGCCGGGGGCCCTCATCCCAGGTG ATCCGCAGGCCATGAGCCAGCCCAACAGAGGTCCCTCACCTTTCAGTCCTGTCCAGCTGCATCAGCTTCG AGCTCAGATTTTAGCTTATAAAATGCTGGCCCGAGGCCAGCCCCTCCCCGAAACGCTGCAGCTTGCAGTC CAGGGGAAAAGGACGTTGCCTGGCTTGCAGCAACAACAGCAGCAGCAACAGCAGCAGCAGCAGCAGCAGC AGCAGCAGCAGCAGCAGCAACAGCAGCCGCAGCAGCAGCCGCCGCAACCACAGACGCAGCAACAACAGCA GCCGGCCCTTGTTAACTACAACAGACCATCTGGCCCGGGGCGGAGCTGAGCGGCCCGAGCACCCCGCAG AAGCTGCCGGTGCCCGCGCCCGGCGGCCGGCCCTCGCCCGGCCCCCCGCAGCGCGCAGCCGCCCGCGG CCGCAGTGCCCGGGCCCTCAGTGCGCAGCCGGCCCCGGGGCAGCCCTCGCCCGTCCTCCAGCTGCAGCA GAAGCAGAGCCGCATCAGCCCCATCCAGAAACCGCAAGGCCTGGACCCCGTGGAAATTCTGCAAGAGCGG GAATACAGACTTCAGGCCCGCATAGCTCATAGGATACAAGAACTGGAAAATCTGCCTGGCTCTTTGCCAC CAGATTTAAGAACCAAAGCAACCGTGGAACTAAAAGCACTTCGGTTACTCAATTTCCAGCGTCAGCTGAG ACAGGAGGTGGTGGCCTGCATGCGCAGGGACACGACCCTGGAGACGGCTCTCAACTCCAAAGCATACAAA CGGAGCAAGCGCCAGACTCTGAGAGAAGCTCGCATGACCGAGAAGCTGGAGAAGCAGCAGAAGATTGAGC AGGAGAGGAAACGCGCGTCAGAAACACCAGGAATACCTGAACAGTATTTTGCAACATGCAAAAGATTTTAA GGAATATCATCGGTCTTGGCCGGAAAGATCCAGAAGCTCTCCAAAGCAGTGGCAACTTGGCATGCCAAC ACTGAAAGAGAGCAGAAGAGGACAGAGCGGATTGAAAAGGAGAGAGAATGCGGCGACTGATGGCTGAAG ATGAGGAGGGTTATAGAAAACTGATTGATCAAAAGAAAGACAGGCGTTTAGCTTACCTTTTGCAGCAGAC CGATGAGTATGTAGCCAATCTGACCAATCTGGTTTGGGAGCACAAGCAAGCCCAGGCAGCCAAAGAGAAG AAGAAGAGGAGGAGGAGGAAGAAGAAGGCTGAGGAGAATGCAGAGGGTGGGGAGTCTGCCCTGGGACCGG ATGGAGAGCCCATAGATGAGAGCAGCCAGATGAGTGACCTCCCTGTCAAAGTGACTCACACAGAAACCGG CAAGGTTCTGTTCGGACCAGAAGCACCCAAAGCAAGTCAGCTGGACGCCTGGCTGGAAATGAATCCTGGT TATGAAGTTGCCCCTAGATCTGACAGTGAAGAGAGTGATTCTGATTATGAGGAAGAGGATGAGGAAGAAG AGTCCAGTAGGCAGGAAACCGAAGAGAAAATACTCCTGGATCCAAATAGCGAAGAAGTTTCTGAGAAGGA TGCTAAGCAGATCATTGAGACAGCTAAGCAAGACGTGGATGATGAATACAGCATGCAGTACAGTGCCAGG GGCTCCCAGTCCTACTACACCGTGGCTCATGCCATCTCGGAGAGGGTGGAGAAACAGTCTGCCCTCCTAA TTAATGGGACCCTAAAGCATTACCAGCTCCAGGGCCTGGAATGGATGGTTTCCCTGTATAATAACAACTT GAACGGAATCTTAGCCGATGAAATGGGGCTTGGAAAGACCATACAGACCATTGCACTCATCACTTATCTG ATGGAGCACAAAAGACTCAATGGCCCCTATCTCATCATTGTTCCCCTTTCGACTCTATCTAACTGGACAT ATGAATTTGACAAATGGGCTCCTTCTGTGGTGAAGATTTCTTACAAGGGTACTCCTGCCATGCGTCGCTC CCTTGTCCCCCAGCTACGGAGTGGCAAATTCAATGTCCTCTTGACTACTTATGAGTATATTATAAAAGAC AAGCACATTCTTGCAAAGATTCGGTGGAAATACATGATAGTGGACGAAGGCCACCGAATGAAGAATCACC ACTGCAAGCTGACTCAGGTCTTGAACACTCACTATGTGGCCCCCAGAAGGATCCTCTTGACTGGGACCCC GCTGCAGAATAAGCTCCCTGAACTCTGGGCCCTCCTCAACTTCCTCCTCCCAACAATTTTTAAGAGCTGC AGCACATTTGAACAATGGTTCAATGCTCCATTTGCCATGACTGGTGAAAGGGTGGACTTAAATGAAGAAG AAACTATATTGATCATCAGGCGTCTACATAAGGTGTTAAGACCATTTTTACTAAGGAGACTGAAGAAAGA AGTTGAATCCCAGCTTCCCGAAAAAGTGGAATATGTGATCAAGTGTGACATGTCAGCTCTGCAGAGATT CTGTATCGCCATATGCAAGCCAAGGGATCCTTCTCACAGATGGTTCTGAGAAAGATAAGAAGGGGAAAG GAGGTGCTAAGACACTTAATGAACACTATTATGCAGTTGAGAAAAATCTGCAACCACCCATATATGTTTCA GCACATTGAGGAATCCTTTGCTGAACACCTAGGCTATTCAAATGGGGTCATCAATGGGGGCTGAACTGTAT CGGGCCTCAGGAAGTTTGAGCTGCTTGATCGTATTCTGCCAAAATTGAGAGCGACTAATCACCGAGTGC TGCTTTTCTGCCAGACATCTCTCATGACCATCATGGAGGATTATTTTGCTTTTCGGAACTTCCTTTA CCTACGCCTTGATGGCACCACCAAGTCTGAAGATCGTGCTGCTTTGCTGAAGAAATTCAATGAACCTGGA TCCCAGTATTTCATTTTCTTGCTGAGCACAAGAGCTGGTGGCCTGGGCTTAAATCTTCAGGCAGCTGATA CAGTGGTCATCTTTGACAGCGACTGGAATCCTCATCAGGATCTGCAGGCCCAAGACCGAGCTCACCGCAT CGGGCAGCAGAACGAGGTCCGGGTACTGAGGCTCTGTACCGTGAACAGCGTGGAGGAAAAGATCCTCGCG GCCGCAAAATACAAGCTGAACGTGGATCAGAAAGTGATCCAGGCGGGCATGTTTGACCAAAAGTCTTCAA GCCACGAGCGGAGGGCATTCCTGCAGGCCATCTTGGAGCATGAGGAGGAAAATGAGGAAGAAGATGAAGT ACCGGACGATGAGACTCTGAACCAAATGATTGCTCGACGAGAAGAAGAATTTGACCTTTTTATGCGGATG GACATGGACCGGCGGAGGGAAGATGCCCGGAACCCGAAACGGAAGCCCCGTTTAATGGAGGAGGATGAGC TGCCCTCCTGGATCATTAAGGATGACGCTGAAGTAGAAAGGCTCACCTGTGAAGAAGAGGAGGAGAAAAT ATTTGGGAGGGGGTCCCGCCAGCGCCGTGACGTGGACTACAGTGACGCCCTCACGGAGAAGCAGTGGCTA AGGGCCATCGAAGACGGCAATTTGGAGGAAATGGAAGAGGAAGTACGGCTTAAGAAGCGAAAAAGACGAA GAAATGTGGATAAAGATCCTGCAAAAGAAGATGTGGAAAAAGCTAAGAAGAGAAGAGGCCGCCCTCCCGC TGAGAAACTGTCACCAAATCCCCCCAAACTGACAAAGCAGATGAACGCTATCATCGATAACTGTGATAAAC TACAAAGATAGGTGTAACGTGGAGAAGGTGCCCAGTAATTCTCAGTTGGAAATAGAAGGAAACAGTTCAG GGCGACAGCTCAGTGAAGTCTTCATTCAGTTACCTTCCAAGGAAAGAATTACCAGAATACTATGAATTAAT TAGGAAGCCAGTGGATTTCAAAAAAATAAAGGAAAGGATTCGTAATCATAAGTACCGGAGCCTAGGCGAC CTGGAGAAGGATGTCATGCTTCTCTGTCACAACGCTCAGACGTTCAACCTGGAGGGATCCAGATCTATG AAGACTCCATCGTCTTACAGTCAGTGTTTAAGAGTGCCCGGCAGAAATTGCCAAAGAGGAAGAGTG GGATGAAAGCAATGAAGAGGAGGAAGGAAGATGAAGAAGAGTCAGAGTCCGAGGCAAAATCAGTCAAG GTGAAAATTAAGCTCAATAAAAAAGATGACAAAGGCCCGGGACAAAGGGAAGGCAAGAAAAGGCCAAATC GAGGAAAAGCCAAACCTGTAGTGAGCGATTTTGACAGCGATGAGGAGCAGGATGAACGTGAAACGTCAGA AGGAAGTGGGACGGATGATGAGTGATCAGTATGGACCTTTTTCCTTGGTAGAACTGAATTCCTTCCTCCC CTGTTCCATTTCTACCCAGTGAGTTCATTGTCATATAGGCACTGGGTTGTTTCTATATCATCATCGTCT ATAAACTAGCTTTAGGATAGTGCCAGACAAACATATGATATCATGGTGTAAAAAACACACACATACACAA ATATTTGTAACATATTGTGACCAAATGGGCCTCAAAGATTCAGATTGAAACAAACAAAAAGCTTTTGATG GAAAATATGTGGGTGGATAGTATATTTCTATGGGTGGGTCTAATTTGGTAACGGTTTGATTGTGCCTGGT TTTATCACCTGTTCAGATGAGAAGATTTTTGTCTTTTGTAGCACTGATAACCAGGAGAAGCCATTAAAAG CCACTGGTTATTTTATTTTTCATCAGGCAATTTTCGAGGTTTTTATTTGTTCGGTATTGTTTTTTTACAC TGTGGTACATATAAGCAACTTTAATAGGTGATAAATGTACAGTAGTTAGATTTCACCTGCATATACATTT TTCCATTTTATGCTCTATGATCTGAACAAAAGCTTTTTGAATTGTATAAGATTTATGTCTACTGTAAACA TTGCTTAATTTTTTTGCTCTTGATTTAAAAAAAAGTTTTGTTGAAAGCGCTATTGAATATTGCAATCTAT ATAGTGTATTGGATGGCTTCTTTTGTCACCCTGATCTCCTATGTTACCAATGTGTATCGTCTCCTTCTCC CTAAAGTGTACTTAATCTTTGCTTTCTTTGCACAATGTCTTTGGTTGCAAGTCATAAGCCTGAGGCAAAT AAAATTCCAGTAATTTCGAAGAATGTGGTGTTGGTGCTTTCCTAATAAAGAAATAATTTAGCTTGACAAA AAAAAAAAAAAA The term "BRM" also refers to naturally occurring variants of wild-type human BRM protein, such as proteins having at least 85% identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity or more) to the amino acid sequence of wild-type BRM set forth in SEQ ID NO: 4 (Uniprot Accession No. P51531, www.uniprot.org / uniprot / P51531.fasta).

[0107] SEQ ID NO:4. MSTPTDPGAMPHPGPPSPGPGPSPGPILGPSPGPGPSPGSVHSMMGPSPGPPSVSHPMPTM GSTDFPQEGMHQMHKPIDGIHDKGIVEDIHCGSMKGTGMRPPHPGMGPPQSPMDQHSQGY MSPHPSPLGAPEHVSSPMSGGGPTPPQMPPSQPGALIPGDPQAMSQPNRGPSPFSPVQLH QLRAQILAYKMLARGQPLPETLQLAVQGKRTLPGLQQQQQQQQQQQQQQQQQQQQQQPQ QQPPQPQTQQQQQPALVNYNRPSGPGPELSGPSTPQKLPVPAPGGRPSPAPPAAAQPPAA AVPGPSVPQPAPGQPSPVLQLQQKQSRISPIQKPQGLDPVEILQEREYRLQARIAHRIQE LENLPGSLPPDLRTKATVELKALRLLNFQRQLRQEVVACMRRDTTLETALNSKAYKRSKR QTLREARMTEKLEKQQKIEQERKRRQKHQEYLNSILQHAKDFKEYHRSVAGKIQKLSKAV ATWHANTEREQKKETERIEKERMRRLMAEDEEGYRKLIDQKKDRRLAYLLQQTDEYVANL TNLVWEHKQAQAAKEKKKRRRRKKKAEENAEGGESALGPDGEPIDESSQMSDLPVKVTHT ETGKVLFGPEAPKASQLDAWLEMNPGYEVAPRSDSEESDSDYEEEDEEEESSRQETEEKI LLDPNSEEVSEKDAKQIIETAKQDVDDEYSMQYSARGSQSYYTVAHAISERVEKQSALLI NGTLKHYQLQGLEWMVSLYNNNLNGILADEMGLGKTIQTIALITYLMEHKRLNGPYLIIV PLSTLSNWTYEFDKWAPSVVKISYKGTPAMRRSLVPQLRSGKFNVLLTTYEYIIKDKHIL AKIRWKYMIVDEGHRMKNHHCKLTQVLNTHYVAPRRILLTGTPLQNKLPELWALLNFLLP TIFKSCSTFEQWFNAPFAMTGERVDLNEEETILIIRRLHKVLRPFLLRRLKKEVESQLPE KVEYVIKCDMSALQKILYRHMQAKGILLTDGSEKDKKGKGGAKTLMNTIMQLRKICNHPY MFQHIEESFAEHLGYSNGVINGAELYRASGKFELLDRILPKLRATNHRVLLFCQMTSLMT IMEDYFAFRNFLYLRLDGTTKSEDRAALLKKFNEPGSQYFIFLLSTRAGGLGLNLQAADT VVIFDSDWNPHQDLQAQDRAHRIGQQNEVRVLRLCTVNSVEEKILAAAKYKLNVDQKVIQ AGMFDQKSSSHERRAFLQAILEHEEENEEEDEVPDDETLNQMIARREEEFDLFMRMDMDR RREDARNPKRKPRLMEEDELPSWIIKDDAEVERLTCEEEEEKIFGRGSRQRRDVDYSDAL TEKQWLRAIEDGNLEEMEEEVRLKKRKRRRNVDKDPAKEDVEKAKKRRGRPPAEKLSPNP PKLTKQMNAIIDTVINYKDRCNVEKVPSNSQLEIEGNSSGRQLSEVFIQLPSRKELPEYY ELIRKPVDFKKIKERIRNHKYRSLGDLEKDVMLLCHNAQTFNLEGSQIYEDSIVLQSVFK SARQKIAKEEESEDESNEEEEEEDEEEESESEAKSVKVKIKLNKKDDKGRDKGKGKKRPNR GKAKPVVSDFDSDEEQDEREQSEGSGTDDE As used herein, the term "BRG1 activity" refers to the activity of the BRG1 enzyme ATPase.

[0108] As used herein, the term "BRG1 loss-of-function mutation" refers to a mutation in BRG1 that results in a protein with reduced activity (e.g., at least 1% reduction in BRG1 activity, e.g., 2%, 5%, 10%, 25%, 50%, or 100% reduction in BRG1 activity). Exemplary BRG1 loss-of-function mutations include, but are not limited to, homozygous BRG1 mutations and deletions at the C-terminus of BRG1.

[0109] As used herein, the term "BRG1 loss-of-function disorder" refers to a disorder (e.g., leukemia (e.g., acute myeloid leukemia)) that exhibits a reduction in BRG1 activity (e.g., at least a 1% reduction in BRG1 activity, e.g., a 2%, 5%, 10%, 25%, 50%, or 100% reduction in BRG1 activity).

[0110] As used herein, "combination therapy" or "combined administration" means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the dose and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents is simultaneous or combined, and the agents may be co-formulated. In some embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, the administration of the two or more agents or combined treatments is such that the reduction in symptoms, or other parameters associated with the disorder, is greater than that observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments may be partially additive, fully additive, or greater than additive (e.g., synergistic). The sequential or substantially simultaneous administration of each therapeutic agent may be effected by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or by different routes, for example, a first therapeutic agent in the combination may be administered by intravenous injection and a second therapeutic agent in the combination may be administered orally.

[0111] The term "CTLA-4 inhibitor" as used herein refers to a compound, such as an antibody, that can inhibit the activity of the protein encoded by the CTLA4 gene in humans. Known CTLA-4 inhibitors include ipilimumab.

[0112] A "decreased level" or "elevated level" of a protein or RNA refers to a decrease or increase, respectively, in protein or RNA levels compared to a reference (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500% or more decrease or increase, respectively, in protein or RNA levels compared to a reference. By "protein level" is meant a decrease or increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%; a decrease or increase of less than about 0.01 fold, about 0.02 fold, about 0.1 fold, about 0.3 fold, about 0.5 fold, about 0.8 fold, or less; or an increase of more than about 1.2 fold, about 1.4 fold, about 1.5 fold, about 1.8 fold, about 2.0 fold, about 3.0 fold, about 3.5 fold, about 4.5 fold, about 5.0 fold, about 10 fold, about 15 fold, about 20 fold, about 30 fold, about 40 fold, about 50 fold, about 100 fold, about 1000 fold, or more. Protein levels can be expressed as mass / volume (e.g., g / dL, mg / mL, μg / mL, ng / mL) or as a percentage of total protein in the sample.

[0113] "Reducing the activity of BAF complex" means reducing the level of activity associated with BAF complex or the downstream effect associated with BAF complex.A non-limiting example of reducing the activity of BAF complex is the activation of Sox2.The activity level of BAF complex can be measured using any method known in the art, for example, the method described in Kadoch et al.Cell,2013,153,71-85, which is incorporated herein by reference.

[0114] As used herein, the term "degrading agent" refers to a small molecule compound that contains a degrading moiety, where the compound interacts with a protein (e.g., BRG1 and / or BRM) in a manner that results in degradation of the protein, e.g., binding of the compound results in, e.g., at least a 5% reduction in the levels of the protein in a cell or subject.

[0115] As used herein, the term "degradation moiety" refers to a moiety whose binding results in degradation of a protein, e.g., BRG1 and / or BRM. In one example, the moiety binds to a protease or ubiquitin ligase that metabolizes a protein, e.g., BRG1 and / or BRM.

[0116] As used herein, a leukemia (e.g., acute myeloid leukemia) that is "determined to be drug resistant" refers to a leukemia (e.g., acute myeloid leukemia) that is drug resistant based on non-responsiveness or reduced responsiveness to chemotherapeutic agents or that is predicted to be drug resistant based on a prognostic assay (e.g., a gene expression assay).

[0117] By "drug resistance" is meant a leukemia (e.g., acute myeloid leukemia) that does not respond or exhibits a reduced response to one or more chemotherapeutic agents (e.g., any agent described herein).

[0118] As used herein, the term "failed to respond to previous therapy" or "refractory to previous therapy" refers to leukemia (e.g., acute myeloid leukemia) that has progressed despite treatment with a therapy.

[0119] "Reducing the activity of BRG1 and / or BRM" means reducing the level of activity or downstream effects associated with BRG1 and / or BRM. A non-limiting example of inhibiting the activity of BRG1 and / or BRM is reducing the level of the BAF complex (e.g., GBAF) in a cell. The activity level of BRG1 and / or BRM can be measured using any method known in the art. In some embodiments, the agent that reduces the activity of BRG1 and / or BRM is a small molecule BRG1 and / or BRM inhibitor. "Reducing the level of BRG1 and / or BRM" means decreasing the level of BRG1 and / or BRM in a cell or a subject. The level of BRG1 and / or BRM can be measured using any method known in the art.

[0120] As used herein, the term "inhibiting BRG and / or BRM" refers to inhibiting or reducing the level or activity of the ATPase catalytic binding domain or bromodomain of a protein. Inhibition of BRG1 and / or BRM can be determined using methods known in the art, such as a BRG and / or BRM ATPase assay, a NanoDSF assay, or a BRG1 and / or BRM luciferase cellular assay.

[0121] By "level" is meant the level of a protein, or of the mRNA encoding the protein, as compared to a reference material. A reference material can be any useful reference material, as defined herein. A "decreased level" or "increased level" of a protein means a decrease or increase in protein level as compared to a reference material (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500% or more decrease or increase, as compared to a reference material). about a 10%, 15%, 20%, 50%, 75%, 100%, or greater than about a 200% decrease or increase, about a 0.01-fold, about a 0.02-fold, about a 0.1-fold, about a 0.3-fold, about a 0.5-fold, about a 0.8-fold decrease or increase, or less than about a 1.2-fold, about a 1.4-fold, about a 1.5-fold, about a 1.8-fold, about a 2.0-fold, about a 3.0-fold, about a 3.5-fold, about a 4.5-fold, about a 5.0-fold, about a 10-fold, about a 15-fold, about a 20-fold, about a 30-fold, about a 40-fold, about a 50-fold, about a 100-fold, or greater increase). Protein levels can be expressed as mass / volume (e.g., g / dL, mg / mL, μg / mL, ng / mL) or as a percentage of the total protein or mRNA in the sample.

[0122] As used herein, the term "inhibitor" refers to any agent that reduces the level and / or activity of a protein (e.g., BRG1 and / or BRM). Non-limiting examples of inhibitors include small molecule inhibitors, degraders, antibodies, enzymes, or polynucleotides (e.g., siRNAs).

[0123] As used herein, the term "LXS196", also known as IDE196, has the structure:

[0124] [ka]

[0125] or a pharma- ceutically acceptable salt thereof. The term "MEK inhibitor" as used herein refers to a compound capable of inhibiting the activity of the mitogen-activated protein kinase enzymes MEK1 or MEK2. The MEK inhibitor may be, for example, selumetinib, binimetinib, or tametinib.

[0126] As used herein, the terms "effective amount," "therapeutically effective amount," and "sufficient amount" of an agent that reduces the level and / or activity of BRG1 and / or BRM (e.g., in a cell or subject) described herein refer to an amount sufficient to produce a beneficial or desired result, including a clinical result, when administered to a subject, including a human, and thus "effective amount" or its synonyms depend on the context in which it is applied. For example, in the context of treating v, it is the amount of an agent that reduces the level and / or activity of BRG1 and / or BRM sufficient to achieve a therapeutic response compared to the response obtained without administration of the agent that reduces the level and / or activity of BRG1 and / or BRM. The amount of a given agent that reduces the level and / or activity of BRG1 and / or BRM described herein that would correspond to such an amount will vary depending on various factors, such as the given agent, pharmaceutical formulation, route of administration, type of disease or disorder, subject identity (e.g., age, sex, and / or weight), or host being treated, but may nevertheless be routinely determined by one of skill in the art. Also, as used herein, a "therapeutically effective amount" of an agent that reduces the level and / or activity of BRG1 and / or BRM of the present disclosure is an amount that produces a beneficial or desired result in a subject compared to a control. As defined herein, a therapeutically effective amount of an agent that reduces the level and / or activity of BRG1 and / or BRM of the present disclosure can be readily determined by a person skilled in the art by routine methods known in the art. Dosage regimens can be adjusted to provide an optimal therapeutic response.

[0127] The term "inhibitory RNA agent" refers to RNA or its analogues that have sufficient sequence complementarity to target RNA to induce RNA interference. Examples also include DNA that can be used to make RNA. RNA interference (RNAi) refers to a sequence-specific or selective process in which a target molecule (e.g., a target gene, protein, or RNA) is downregulated. In general, interfering RNA ("iRNA") is a double-stranded short interfering RNA (siRNA), short hairpin RNA (shRNA), or single-stranded microRNA (miRNA) that leads to catalytic degradation of specific mRNA, and can also be used to reduce or inhibit gene expression.

[0128] The terms "short interfering RNA" and "siRNA" (also known as "small interfering RNA") refer to RNA agents, preferably double-stranded agents, of about 10-50 nucleotides in length, where the strands optionally have overhanging ends containing, e.g., 1, 2, or 3 overhanging nucleotides (or nucleotide analogs) capable of inducing or mediating RNA interference. Naturally occurring siRNAs are generated from longer dsRNA molecules (e.g., >25 nucleotides in length) by the cellular RNAi machinery (e.g., Dicer or its homologs).

[0129] As used herein, the term "shRNA" refers to an RNA agent having a stem-loop structure comprising first and second regions of complementary sequence, where the degree of complementarity and orientation of the regions are sufficient for base pairing to occur between the regions, and where the first and second regions are joined by a loop region, the loop resulting from a lack of base pairing between nucleotides (or nucleotide analogs) in the loop region.

[0130] The terms "miRNA" and "microRNA" refer to an RNA agent, preferably a single-stranded agent, of about 10-50 nucleotides in length, preferably about 15-25 nucleotides in length, capable of inducing or mediating RNA interference. Naturally occurring miRNAs are generated from stem-loop precursor RNAs (i.e., pre-miRNAs) by Dicer. As used herein, the term "Dicer" includes Dicer as well as any Dicer ortholog or homolog capable of processing dsRNA structures into siRNA, miRNA, siRNA-like or miRNA-like molecules. The term microRNA ("miRNA") is used interchangeably with "small temporal RNA" ("stRNA") based on the fact that naturally occurring miRNAs have been found to be expressed in a temporal manner (e.g., during development).

[0131] As used herein, the term "antisense" refers to a nucleic acid comprising a polynucleotide that is sufficiently complementary to all or a portion of a gene, primary transcript, or processed mRNA so as to interfere with the expression of an endogenous gene (e.g., BRG1 and / BRM). A "complementary" polynucleotide is one that is capable of base pairing according to the standard Watson-Crick rules of complementarity. Specifically, purines base pair with pyrimidines, forming combinations of guanine paired with cytosine (G:C), adenine paired with either thymine (A:T), or adenine paired with uracil (A:U) in the case of DNA. It is understood that two polynucleotides can hybridize to each other even if they are not completely complementary to each other, provided that each has at least one region that is substantially complementary to each other.

[0132] The term "antisense nucleic acid" includes single-stranded RNA that can be transcribed to generate antisense RNA as well as double-stranded DNA expression cassettes. An "active" antisense nucleic acid is an antisense RNA molecule that can selectively hybridize to a primary transcript or mRNA encoding a polypeptide having at least 80% (e.g., 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity, or more) sequence identity with a targeted polypeptide sequence (e.g., BRG1 and / or BRM polypeptide sequence). The antisense nucleic acid can be complementary to the entire coding strand, or only a portion thereof. In another embodiment, the antisense nucleic acid molecule is antisense to a "coding region" of the coding strand of a nucleotide sequence. The term "coding region" refers to the region of a nucleotide sequence that contains codons that are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a "noncoding region" of the coding strand of a nucleic acid sequence. The term "noncoding region" refers to the 5' and 3' sequences adjacent to the coding region that are not translated into amino acids (i.e., also referred to as the 5' and 3' untranslated regions). The antisense nucleic acid molecule can be complementary to the entire coding region of an mRNA, or can be antisense to only a portion of the coding or noncoding region of an mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site. The antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length.

[0133] "Percent sequence identity" with respect to a reference polynucleotide or polypeptide sequence is defined as the percentage of nucleic acids or amino acids in a candidate sequence that are identical to those in a reference polynucleotide or polypeptide sequence, after aligning the sequences and introducing gaps as necessary to achieve the maximum percent sequence identity. Alignment for the purpose of determining percent nucleic acid or amino acid sequence identity can be achieved in various ways that are within the capabilities of one of the skilled artisans, for example, using publicly available computer software such as BLAST, BLAST-2, or Megalign software. Those skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithms required to achieve maximum alignment over the full length of the sequences being compared. For example, percent sequence identity values ​​can be generated using the sequence comparison computer program BLAST. As an example, the percent sequence identity of a given nucleic acid or amino acid sequence A to, with, or against a given nucleic acid or amino acid sequence B (which may alternatively be expressed as a given nucleic acid or amino acid sequence A having a certain percent sequence identity to, with, or against a given nucleic acid or amino acid sequence B) is calculated as follows: 100×(fraction X / Y) where X is the number of nucleotides or amino acids scored as identical matches by a sequence alignment program (e.g., BLAST) in a programmatic alignment of A and B, and Y is the total number of nucleic acids in B. If the length of nucleic acid or amino acid sequence A is not equal to the length of nucleic acid or amino acid sequence B, then the percent sequence identity of A to B will not be equal to the percent sequence identity of B to A.

[0134] As used herein, the term "pharmaceutical composition" refers to a composition that contains a compound described herein formulated with a pharma- ceutical acceptable excipient and is suitable for administration to a mammal, e.g., a human. Typically, pharmaceutical compositions are manufactured or sold by approval of a government regulatory agency as part of a therapeutic regimen for the treatment of a mammalian disease. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., tablet, capsule, caplet, gelcap, or syrup), for topical administration (e.g., as a cream, gel, lotion, or ointment), for intravenous administration (e.g., as a sterile solution free of particulate embolic material and in a solvent system suitable for intravenous use), or in any other pharma- ceutical acceptable formulation.

[0135] "Pharmaceutically acceptable excipient" as used herein refers to any component other than the compounds described herein (e.g., a vehicle that can suspend or dissolve active compounds) that has the properties of being substantially non-toxic and non-inflammatory in patients.Excipients can include, for example, anti-adhesive agents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (coloring agents), emollients, emulsifiers, bulking agents (diluents), film-forming agents or coating agents, flavorings, flavoring agents, glidants (glidants), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water for hydration.

[0136] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt of any of the compounds described herein. For example, pharmaceutically acceptable salts of any of the compounds described herein include salts that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, or allergic response, within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or can be prepared separately by reacting the free base group with a suitable organic acid.

[0137] The compounds described herein may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts.These salts may be acid addition salts, including inorganic or organic acids, or salts may be prepared from inorganic or organic bases in the case of the acidic form of the compounds described herein.Often, compounds are prepared or used as pharmaceutically acceptable salts, which are prepared as addition products of pharmaceutically acceptable acids or bases.Suitable pharmaceutically acceptable acids and bases, as well as the preparation method of suitable salts, are well known in the art.Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Representative salts include salts of the following acids: lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0138] The term "PKC inhibitor," as used herein, refers to a compound capable of inhibiting the activity of protein kinase C. The PKC inhibitor can be, for example, sotrastaurin or IDE196.

[0139] "Proliferation" as used in this application involves the reproduction or multiplication of similar forms (cells) by constituent (cellular) elements. "Reference" means any useful reference used to compare protein or RNA levels. A reference can be any sample, standard, standard curve, or level used for comparison purposes. A reference can be a normal reference sample or a reference standard or reference level. A "reference sample" can be, for example, a control, e.g., a "normal control" or a predetermined negative control value, such as a previous sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., cell or tissue) from a subject without a disease; a sample from a subject diagnosed with a disease but not yet treated with a compound of the invention; a sample from a subject being treated with a compound of the invention; or a sample of a known normal concentration of purified protein or RNA (e.g., any of those described herein). "Reference standard or reference level" means a value or number obtained from a reference sample. A "normal control value" is a predetermined value that indicates a non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range ("between X and Y"), a high threshold ("below X"), or a low threshold ("above X"). A subject having a measured value within the normal control value for a particular biomarker is typically referred to as "within the normal range" for that biomarker. The normal reference standard or level can be a value or number derived from a normal subject without a disease or disorder (e.g., leukemia (e.g., acute myeloid leukemia)); a subject being treated with a compound of the present invention. In a preferred embodiment, the reference sample, standard, or level is matched to the subject sample by at least one of the following criteria: age, weight, sex, stage of disease, and general condition. A standard curve of purified protein or RNA (e.g., any of those described herein) levels within the normal reference range can also be used as a reference.

[0140] As used herein, the term "subject" refers to any organism to which a composition according to the invention may be administered, for example, for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may be a human or animal that is seeking or in need of treatment, is in need of treatment, is undergoing treatment, will be undergoing treatment in the future, or is undergoing treatment by a trained professional for a particular disease or condition.

[0141] As used herein, the terms "treat", "treated" or "treating" refer to a therapeutic procedure or any action aimed at slowing down (alleviating) an undesirable physiological condition, disorder or disease, or obtaining a beneficial or desired clinical outcome. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms; reduction in the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the condition, disorder or disease state; delaying the onset or slowing down the progression of the condition, disorder or disease; improvement or remission (whether partial or complete) of the condition, disorder or disease state; improvement (not necessarily recognized by the patient) of at least one measurable physical parameter; or improvement or amelioration of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without an excessive level of side effects. Treatment also includes prolonging survival compared to the expected survival if not treated. The compounds of the present invention can also be used to "prophylactically treat" or "prevent" a disorder, for example, in subjects at high risk of developing the disorder.

[0142] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Methods and materials for use in this disclosure are described herein. Other suitable methods and materials known in the art may also be used. Materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0143] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will become apparent from the description and from the claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0144] Generally, the present invention provides methods of treating subjects having clinically significant signs and symptoms associated with blood cell differentiation and who have been treated with an agent that reduces the level and / or activity of BRG1 and / or BRM. It has been unexpectedly discovered that some subjects may develop clinically significant signs and symptoms associated with blood cell differentiation (e.g., differentiation syndrome) while receiving an agent of the following structure (e.g., for the treatment of leukemia, e.g., acute myeloid leukemia):

[0145] [ka]

[0146] Without wishing to be bound by theory, it is believed that reducing the level and / or activity of BRG1 and / or BRM (e.g., using the compounds shown above) involves an interaction between the SPI1 transcription factor and BAF, thereby affecting bone marrow cell differentiation, which in turn leads to the development of clinically significant signs and symptoms associated with blood cell differentiation. Thus, subjects treated with agents that reduce the level and / or activity of BRG1 and / or BRM and have clinically significant signs and symptoms associated with blood cell differentiation can be treated using the methods described herein.

[0147] method The methods disclosed herein can be used to treat subjects with clinically significant signs and symptoms associated with blood cell differentiation. For example, the subject can be suspected of having differentiation syndrome. The clinically significant signs and symptoms (e.g., symptoms of differentiation syndrome) can be one or more of the following: fever of unknown origin, skin rash, hypoxia, respiratory dysfunction, interstitial lung infiltrates, pleural and / or pericardial effusion, weight gain, renal failure, dyspnea, clinical deterioration, fluid in or around the lungs, fluid around the heart, swelling in the legs, increased bilirubin, and increased liver enzymes. Typically, subjects receiving treatment with agents that reduce the levels and / or activity of BRG1 and / or BRM can be monitored for changes in blood samples, such as absolute neutrophil count (ANC), platelet count, or white blood cell (WBC) count. Thus, alternatively or additionally, blood samples from the subject can be tested to determine absolute neutrophil count (ANC) and / or platelet count. An increase in ANC of at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%) occurring upon therapy with an agent that reduces the level and / or activity of BRG1 and / or BRM may be a clinically significant sign or symptom associated with blood cell differentiation (e.g., may be a symptom of differentiation syndrome). An increase in platelet count of at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%) occurring upon therapy with an agent that reduces the level and / or activity of BRG1 and / or BRM may be a clinically significant sign or symptom associated with blood cell differentiation (e.g., may be a symptom of differentiation syndrome). The subject may also, or alternatively, suffer from non-infectious leukocytosis (e.g., a white blood cell (WBC) count of 25 or more). × 10 9 / L (e.g., 30 × 10 9 / L) or >15% from baseline × 10 9Any clinically significant signs and symptoms associated with blood cell differentiation (e.g., differentiation syndrome symptoms) may be manifested upon treatment (e.g., upon treatment with an agent that reduces the level and / or activity of BRG1 and / or BRM).

[0148] Typically, treatment of clinically significant signs and symptoms associated with blood cell differentiation (e.g., differentiation syndrome symptoms) can be initiated upon the appearance of any one of the clinically significant signs and symptoms associated with blood cell differentiation (e.g., differentiation syndrome symptoms).

[0149] The methods of the invention may include administration (preferably systemic administration) of a corticosteroid (e.g., a glucocorticoid, e.g., a high-dose corticosteroid, e.g., a high-dose glucocorticoid). High-dose regimens of corticosteroids are well known in the art. For example, a high-dose systemic corticosteroid regimen may be intravenous administration of dexamethasone, e.g., at a dose of 10 mg, e.g., every 12 hours. For example, a high-dose systemic corticosteroid regimen may be intravenous or intramuscular administration of prednisone, prednisolone, methylprednisolone, or a pharmaceutically acceptable salt thereof, e.g., at a dose of at least 40 mg (e.g., 40 mg to 60 mg or 40 mg to 125 mg), e.g., daily. Typically, methylprednisolone is administered as a pharmaceutically acceptable salt of methylprednisolone succinate. Corticosteroid therapy (eg, systemic corticosteroids, eg, high-dose systemic corticosteroids) may be continued for at least 3 days (eg, until signs and symptoms have resolved).

[0150] The methods of the invention can include administration (e.g., oral administration) of hydroxyurea (e.g., for subjects with symptoms of non-infectious leukocytosis). Hydroxyurea can be administered, for example, at a dose of at least 2 grams (e.g., 2-4 grams or 2-3 grams), for example, twice daily or three times daily.

[0151] The method of the present invention may include administration (preferably systemic administration) of a diuretic (e.g., furosemide). For example, the systemic diuretic regimen may be intravenous or intramuscular administration of furosemide, e.g., at a dose of 20 mg or 40 mg, administered slowly, e.g., over 1 to 2 minutes. For example, the systemic diuretic regimen may be intravenous or intramuscular administration of furosemide or a pharma- ceutically acceptable salt thereof, e.g., at a dose of at least 20 mg (e.g., 20 mg to 40 mg). For example, the second dose of diuretic may be intravenous or intramuscular administration of furosemide or a pharma- ceutically acceptable salt thereof, e.g., at a dose of at least 20 mg (e.g., 20 mg to 80 mg). For example, the systemic diuretic regimen may be oral administration of furosemide, e.g., at a dose of at least 20 mg (e.g., 20 mg to 80 mg).

[0152] If clinically significant signs and symptoms associated with blood cell differentiation or symptoms of differentiation syndrome persist for at least 48 hours (e.g., at least 3 days) after the start of corticosteroid administration, administration of the agent that reduces the level and / or activity of BRG1 and / or BRM may be interrupted. If clinically significant signs and symptoms associated with blood cell differentiation or symptoms of differentiation syndrome persist for at least 48 hours (e.g., at least 3 days) after the start of hydroxyurea administration, administration of the agent that reduces the level and / or activity of BRG1 and / or BRM may be interrupted. If clinically significant signs and symptoms associated with blood cell differentiation or symptoms of differentiation syndrome persist for at least 48 hours (e.g., at least 3 days) after the start of furosemide administration, administration of the agent that reduces the level and / or activity of BRG1 and / or BRM may be interrupted. If clinically significant signs and symptoms associated with blood cell differentiation, or symptoms of differentiation syndrome, persist for at least 48 hours (e.g., at least 3 days) after the subject has undergone leukapheresis, administration of the agent that reduces the level and / or activity of BRG1 and / or BRM may be discontinued.

[0153] If administration of an agent that reduces the level and / or activity of BRG1 and / or BRM is discontinued, its administration may be resumed, for example, if clinically significant signs and symptoms associated with blood cell differentiation (e.g., differentiation syndrome symptoms) improve, for example, to grade 2 or less. Grade 1 differentiation syndrome is mild differentiation syndrome, grade 2 differentiation syndrome is moderate differentiation syndrome, grade 3 differentiation syndrome is severe differentiation syndrome, and grade 4 is life-threatening differentiation syndrome.

[0154] Without being bound by theory, compounds useful as agents that decrease the level and / or activity of BRG1 and / or BRM are believed to exert their ability by modulating the level, state, and / or activity of the BAF complex, i.e., inhibiting the activity of the BRG1 and / or BRM proteins within the BAF complex in a mammal. BAF complex-associated disorders include, but are not limited to, BRG1 loss-of-function mutation-associated disorders.

[0155] Treating leukemia (e.g., acute myeloid leukemia) according to the methods described herein can result in an increase in the average survival time of a population of subjects treated according to the present invention compared to a population of untreated subjects. For example, the average survival time is extended by more than 30 days (more than 60 days, 90 days, or 120 days). The increase in the average survival time of a population can be measured by any reproducible means. The increase in the average survival time of a population can be measured, for example, by calculating the average survival time of a population after starting treatment with a compound of the present invention. The increase in the average survival time of a population can also be measured, for example, by calculating the average survival time of a population after completing a first treatment with a pharma- ceutically acceptable salt of the present invention.

[0156] Treating leukemia (e.g., acute myeloid leukemia) can also result in a reduction in the mortality rate of a population of treated subjects compared to an untreated population. For example, the mortality rate is reduced by more than 2% (e.g., more than 5%, 10%, or 25%). The reduction in the mortality rate of a population of treated subjects can be measured by any reproducible means, for example, by calculating the average number of disease-related deaths per unit time for a population after the start of treatment with a pharmaceutically acceptable salt of the present invention. The reduction in the mortality rate of a population can also be measured by, for example, calculating the average number of disease-related deaths per unit time for a population after the completion of a first treatment with a pharmaceutically acceptable salt of the present invention.

[0157] BRG1 and / or BRM reducer The agents described herein that reduce the level and / or activity of BRG1 and / or BRM in a cell can be antibodies, proteins (such as enzymes), polynucleotides, or small molecule compounds. The agents reduce the level of an activity associated with BRG1 and / or BRM, or an associated downstream effect, or reduce the level of BRG1 and / or BRM in a cell or subject.

[0158] In some embodiments, the agent that reduces the level and / or activity of BRG1 and / or BRM in a cell is an enzyme, a polynucleotide, or a small molecule compound (such as a small molecule BRG1 and / or BRM inhibitor).

[0159] antibody The agent that reduces the level and / or activity of BRG1 and / or BRM can be an antibody or an antigen-binding fragment thereof. For example, the agent that reduces the level and / or activity of BRG1 and / or BRM described herein is an antibody that reduces or inhibits the activity and / or function of BRG1 and / or BRM through binding to BRG1 and / or BRM.

[0160] The production and use of therapeutic antibodies against target antigens (e.g., BRG1 and / or BRM) are known in the art. For methods of producing recombinant antibodies, including antibody engineering, the use of degenerate oligonucleotides, 5'-RACE, phage display, and mutagenesis; antibody testing and characterization; antibody pharmacokinetics and pharmacodynamics; antibody purification and storage, and screening and labeling techniques, see, for example, the references cited herein above, as well as Zhiqiang An (Editor), Therapeutic Monoclonal Antibodies: From Bench to Clinic. 1st Edition. Wiley 2009, and also Greenfield (Ed.), Antibodies: A Laboratory Manual. (Second edition) Cold Spring Harbor Laboratory Press 2013.

[0161] Polynucleotides In some embodiments, the agent that reduces the level and / or activity of BRG1 and / or BRM in a cell is a polynucleotide. In some embodiments, the polynucleotide is an inhibitory RNA molecule that acts, for example, by the RNA interference (RNAi) pathway. The inhibitory RNA molecule can reduce the expression level (e.g., protein level or mRNA level) of BRG1 and / or BRM. For example, the inhibitory RNA molecule includes small interfering RNA (siRNA), small hairpin RNA (shRNA), and / or microRNA (miRNA) that target full-length BRG1 and / or BRM. siRNA is a double-stranded RNA molecule that typically has a length of about 19-25 base pairs. shRNA is an RNA molecule that includes a hairpin turn that reduces expression of a target gene via RNAi. MicroRNA is a non-coding RNA molecule that typically has a length of about 22 nucleotides. miRNA binds to a target site on an mRNA molecule and silences the mRNA, for example, by causing cleavage of the mRNA, destabilization of the mRNA, or inhibition of translation of the mRNA. Degradation is triggered by the enzymatic RNA-induced silencing complex (RISC).

[0162] In some embodiments, the agent that reduces the level and / or activity of BRG1 and / or BRM in a cell is an antisense nucleic acid. Antisense nucleic acids include antisense RNA (asRNA) and antisense DNA (asDNA) molecules, typically about 10-30 nucleotides in length, that recognize a polynucleotide target sequence or sequence portion through hydrogen bonding interactions with the nucleotide bases of the target sequence (e.g., BRG1 and / or BRM). The target sequence can be single- or double-stranded RNA, or single- or double-stranded DNA.

[0163] In some embodiments, the polynucleotide reduces the level and / or activity of a negative regulator of function or a positive regulator of function, hi other embodiments, the polynucleotide reduces the level and / or activity of an inhibitor of a positive regulator of function.

[0164] The polynucleotides of the invention can be modified to include, for example, modified nucleotides (e.g., 2'-fluoro, 2'-o-methyl, 2'-deoxy, unlocked nucleic acid, 2'-hydroxy, phosphorothioate, 2'-thiouridine, 4'-thiouridine, 2'-deoxyuridine). Without being bound by theory, it is believed that certain modifications can increase nuclease resistance and / or serum stability or reduce immunogenicity. The polynucleotides described above can also be provided in specialized forms such as liposomes, microspheres, or applied in gene therapy, or provided in combination with attached moieties. Such attached moieties include polycations such as polylysine, which act as charge neutralizers for the phosphate backbone, or hydrophobic moieties such as lipids (e.g., phospholipids, cholesterol, etc.), which enhance interaction with cell membranes or increase uptake of the nucleic acid. These moieties can be attached to the nucleic acid at the 3' or 5' end and can include bases, sugars, or may be linked via an intramolecular nucleoside bond. Other moieties may be capping groups specifically placed at the 3' or 5' end of the nucleic acid to prevent degradation by nucleases such as exonucleases, RNases, etc. Such capping groups include hydroxyl protecting groups known in the art, including glycols such as polyethylene glycol and tetraethylene glycol. The inhibitory effect of the polynucleotides can be tested in vivo and in vitro using the cell lines or animal-based gene expression systems of the invention. In some embodiments, the polynucleotides decrease the level and / or activity or function of BRG1 and / or BRM. In embodiments, the polynucleotides inhibit expression of BRG1 and / or BRM. In other embodiments, the polynucleotides increase the degradation of BRG1 and / or BRM and / or decrease the stability (i.e., half-life) of BRG1 and / or BRM. The polynucleotides may be chemically synthesized or transcribed in vitro.

[0165] Inhibitory polynucleotides can be designed by methods well known in the art. siRNA, miRNA, shRNA and asRNA molecules with sufficient homology to provide the sequence specificity required to degrade any RNA uniquely can be designed using programs known in the art, including but not limited to those maintained on the websites of Thermo Fisher Scientific, German Cancer Research Center and Ohio State University Wexner Medical Center. Systematic testing of several designed species to optimize inhibitory polynucleotide sequences can be routinely performed by those skilled in the art. Considerations when designing interference polynucleotides include but are not limited to biophysical, thermodynamic and structural considerations, base selectivity at specific positions of the sense strand, and homology. The creation and use of inhibitory therapeutics based on non-coding RNA, such as ribozymes, RNAse P, siRNA and miRNA, are also known in the art, for example, as described in Sioud, RNA Therapeutics: Function, Design, and Delivery (Methods in Molecular Biology). Humana Press 2010. Exemplary inhibitory polynucleotides for use in the methods of the invention are provided below in Table 1. In some embodiments, an inhibitory polynucleotide has a nucleic acid sequence having at least 50% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) sequence identity to the nucleic acid sequence of an inhibitory polynucleotide of Table 1.In some embodiments, the inhibitory polynucleotide has a nucleic acid sequence having at least 70% sequence identity (e.g., 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity or more) to the nucleic acid sequence of an inhibitory polynucleotide in Table 1.

[0166] The construction of vectors for expressing polynucleotides for use in the present invention can be accomplished using prior art techniques that do not require detailed explanation to the skilled artisan. The generation of efficient expression vectors requires the presence of control sequences that control the expression of the polynucleotide. These control sequences include promoter and enhancer sequences, are influenced by specific cellular factors that interact with these sequences, and are well known in the art.

[0167] Gene editing In some embodiments, the agent that reduces the level and / or activity of BRG1 and / or BRM is a component of a gene editing system. For example, the agent that reduces the level and / or activity of BRG1 and / or BRM introduces an alteration in BRG1 and / or BRM (e.g., an insertion, a deletion (e.g., a knockout), a translocation, an inversion, a single point mutation, or other mutation). In some embodiments, the agent that reduces the level and / or activity of BRG1 and / or BRM in a cell is a nuclease. Exemplary gene editing systems include zinc finger nucleases (ZFNs), transcription activator-like effector-based nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR) systems. ZFN, TALEN, and CRISPR-based methods are described, for example, in Gaj et al., Trends Biotechnol. 31(7):397-405 (2013).

[0168] CRISPR refers to a set of clustered regularly interspaced short palindromic repeats (or a system that includes the set). CRISPR system refers to a system derived from CRISPR and Cas (CRISPR associated proteins) or other nucleases that can be used to silence or mutate genes as described herein. CRISPR system is a naturally occurring system found in the genomes of bacteria and archaea. CRISPR loci are composed of alternating repeat sequences and spacer sequences. In naturally occurring CRISPR systems, the spacer is typically a sequence that is foreign to the bacteria (e.g., a plasmid or phage sequence). CRISPR system has been modified for use in gene editing (e.g., altering, silencing, and / or enhancing specific genes) in eukaryotes. See, e.g., Wiedenheft et al., Nature 482(7385):331-338(2012). For example, such modification of the system includes introducing a plasmid containing a specifically designed CRISPR and one or more appropriate Cas proteins into a eukaryotic cell. CRISPR loci are transcribed into RNA and processed by Cas protein into small RNAs that contain repeat sequences flanked by spacers. The RNA acts as a guide to guide Cas protein to silence specific DNA / RNA sequences depending on the spacer sequence. See, for example, Horvath et al., Science 327(5962):167-170(2010); Makarova et al., Biology Direct 1:7(2006); Pennisi, Science 341(6148):833-836(2013). In some examples, CRISPR systems include Cas9 protein, a nuclease that cuts both strands of DNA. See, for example, ibid.

[0169] In some embodiments, in a CRISPR system for use as described herein, e.g., by one or more methods described herein, the spacer of the CRISPR is derived from a target gene sequence, e.g., a BRG1 and / or BRM sequence. In some embodiments, in a CRISPR system for use as described herein, e.g., by one or more methods described herein, the spacer of the CRISPR is derived from a target gene sequence, e.g., a BRG1 sequence. In some embodiments, in a CRISPR system for use as described herein, e.g., by one or more methods described herein, the spacer of the CRISPR is derived from a target gene sequence, e.g., a BRM sequence.

[0170] In some embodiments, the agent that reduces the level and / or activity of BRG1 and / or BRM comprises a guide RNA (gRNA) for use in a CRISPR system for gene editing. Exemplary gRNAs for use in the methods of the present invention are provided in Table 1 below. In embodiments, the agent that reduces the level and / or activity of BRG1 and / or BRM comprises a ZFN that targets (e.g., cleaves) the nucleic acid sequence (e.g., DNA sequence) of BRG1 and / or BRM, or an mRNA encoding the ZFN. In embodiments, the agent that reduces the level and / or activity of BRG1 and / or BRM comprises a TALEN that targets (e.g., cleaves) the nucleic acid sequence (e.g., DNA sequence) of BRG1, or an mRNA encoding the TALEN. In embodiments, the agent that reduces the level and / or activity of BRG1 and / or BRM comprises a TALEN that targets (e.g., cleaves) the nucleic acid sequence (e.g., DNA sequence) of BRG1, or an mRNA encoding the TALEN. In embodiments, an agent that reduces the level and / or activity of BRG1 and / or BRM comprises a TALEN that targets (e.g., cleaves) a nucleic acid sequence (e.g., a DNA sequence) of a BRM, or an mRNA encoding a TALEN.

[0171] For example, gRNAs can be used in CRISPR systems to engineer modifications of genes (e.g., BRG1 and / or BRM). In other examples, ZFNs and / or TALENs can be used to engineer modifications of genes (e.g., BRG1 and / or BRM). Exemplary modifications include insertions, deletions (e.g., knockouts), translocations, inversions, single point mutations, or other mutations. Modifications can be introduced into genes in cells, for example, in vitro, ex vivo, or in vivo. In some embodiments, the modification reduces (e.g., knocks down or knocks out) the level and / or activity of BRG1 and / or BRM, e.g., the modification is a negative regulator of function. In yet another example, the modification corrects a defect (e.g., a mutation that causes a defect) in BRG1 and / or BRM. In yet another example, the modification corrects a defect (e.g., a mutation that causes a defect) in BRG1. In yet another example, the modification corrects a defect (e.g., a mutation that causes a defect) in BRM.

[0172] In certain embodiments, the CRISPR system is used to edit (e.g., add or delete base pairs) target genes, such as BRG1 and / or BRM. In other embodiments, the CRISPR system is used to introduce a premature stop codon, e.g., thereby reducing expression of the target gene. In yet other embodiments, the CRISPR system is used to reversibly turn off the target gene, e.g., similar to RNA interference. In embodiments, the CRISPR system is used to guide Cas to the promoter of the target gene, e.g., BRG1 and / or BRM, thereby sterically inhibiting RNA polymerase. In embodiments, the CRISPR system is used to guide Cas to the promoter of the target gene, e.g., BRG1, thereby sterically inhibiting RNA polymerase. In embodiments, the CRISPR system is used to guide Cas to the promoter of the target gene, e.g., BRM, thereby sterically inhibiting RNA polymerase.

[0173] In some embodiments, a CRISPR system can be generated to edit BRG1 and / or BRM using techniques described, for example, in U.S. Publication No. 20140068797; Cong et al., Science 339(6121):819-823 (2013); Tsai, Nature Biotechnol., 32(6):569-576 (2014); and U.S. Patent Nos. 8,871,445, 8,865,406, 8,795,965, 8,771,945, and 8,697,359.

[0174] In some embodiments, CRISPR interference (CRISPRi) technology can be used to suppress transcription of specific genes, such as genes encoding BRG1 and / or BRM. In CRISPRi, an engineered Cas9 protein (e.g., nuclease-deficient dCas9, or a dCas9 fusion protein, such as a dCas9-KRAB or dCas9-SID4X fusion) can pair with a sequence-specific guide RNA (sgRNA). The Cas9-gRNA complex can inhibit RNA polymerase, thereby preventing transcription elongation. The complex can also inhibit transcription initiation by preventing the binding of transcription factors. The CRISPRi method is specific, has minimal off-target effects, and is multiplexable, e.g., multiple genes can be suppressed simultaneously (e.g., using multiple gRNAs). The CRISPRi method also allows for reversible gene suppression.

[0175] In some embodiments, CRISPR-mediated gene activation (CRISPRa) can be used for transcriptional activation of, for example, one or more genes described herein, for example, genes that inhibit BRG1 and / or BRM. In CRISPRa technology, dCas9 fusion proteins recruit transcriptional activators. For example, dCas9 can be used to recruit a polypeptide (e.g., an activation domain) such as VP64 or p65 activation domain (p65D) and can be used with sgRNA (e.g., a single sgRNA or multiple sgRNAs) to activate one or more genes, for example, endogenous gene(s). Using multiple sgRNAs can recruit multiple activators, which can increase activation efficiency. Various activation domains and single or multiple activation domains can be used. In addition to engineering dCas9 to recruit activators, sgRNAs can also be engineered to recruit activators. For example, RNA aptamers can be incorporated into sgRNAs to recruit proteins (e.g., activation domains) such as VP64. In some instances, the synergistic activation mediator (SAM) system can be used for transcriptional activation. In SAM, the MS2 aptamer is added to the sgRNA. MS2 recruits the MS2 coat protein (MCP) fused to p65AD and heat shock factor 1 (HSF1). CRISPRi and CRISPRa technologies are described in more detail, for example, in Dominguez et al., Nat. Rev. Mol. Cell Biol. 17(1):5-15 (2016), which is incorporated herein by reference.

[0176] small molecule compound In some embodiments of the invention, the agent that reduces the level and / or activity of BRG1 and / or BRM in a cell is a small molecule compound. In some embodiments, the small molecule compound has a structure of Formulas I-III.

[0177] In some embodiments, the small molecule BRG1 and / or BRM inhibitor is a compound having the structure of Formula I, or a pharma- ceutically acceptable salt thereof:

[0178] [ka]

[0179] wherein m is 0, 1, 2, 3, or 4; X 1 is N or CH; Each R 1 are independently selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 It is aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino.

[0180] In some embodiments, the small molecule BRG1 and / or BRM inhibitor is a compound having the structure of Formula II, or a pharma- ceutically acceptable salt thereof:

[0181] [ka]

[0182] In the formula, R 2 is substituted with hydroxy, and optionally independently, halo, cyano, trifluoromethyl, trifluoromethoxy, C 1-3 Alkyl, and C 1-3 phenyl substituted with one or more groups selected from the group consisting of alkoxy; R 3 -R a , -OR a , -N(R a )2, -S(O)2R aand -C(O)-N(R a ) 2 selected from the group consisting of Each R a are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 15-membered carbocyclyl, and 3- to 15-membered heterocyclyl, each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 15-membered carbocyclyl, and 3- to 15-membered heterocyclyl are optionally represented by R b , oxo, halo, -NO2, -N(R b )2, -CN, -C(O)-N(R b )2, -S(O)-N(R b )2, -S(O)2-N(R b )2, -OR b , -SR b , -OC(O)-R b , -C(O)-R b , -C(O)-OR b , -S(O)-R b , -S(O)2-R b , -N(R b )-C(O)-R b , -N(R b )-S(O)-R b , -N(R b )-C(O)-N(R b )2, and -N(R b )-S(O)2-R b and is substituted with one or more groups independently selected from the group consisting of: Each R b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 alkoxy, 3- to 15-membered carbocyclyl, and 3- to 15-membered heterocyclyl, each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, 3- to 15-membered carbocyclyl, and 3- to 15-membered heterocyclyl are optionally represented by Rc or two R b are optionally substituted, together with the nitrogen to which they are attached, with one or more groups independently selected from the group consisting of oxo and halo, and C 1-3 forming a heterocyclyl optionally substituted with one or more groups independently selected from alkyl; Each R c are independently oxo, halo, -NO2, -N(R d )2, -CN, -C(O)-N(R d )2, -S(O)-N(R d )2, -S(O) 2- N(R d )2, -SR d , -OC(O)-R d , -C(O)-R d , -C(O)-OR d , -S(O)-R d , -S(O) 2- R d , -N(R d )-C(O)-R d , -N(R d )-S(O)-R d , -N(R d )-C(O)-N(R d )2, -N(R d )-S(O) 2- R d , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 15-membered carbocyclyl, and 3- to 15-membered heterocyclyl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 15-membered carbocyclyl, and 3- to 15-membered heterocyclyl are R d , oxo, halo, -NO2, -N(R d )2, -CN, -C(O)-N(R d )2, -S(O)-N(R d )2, -S(O)2-N(R d )2, -OR d , -SR d, -OC(O)-R d , -C(O)-R d , -C(O)-R d , -S(O)-R d , -S(O)2-R d , -N(R d )-C(O)-R d , -N(R d )-S(O)-R d , -N(R d )-C(O)-N(R d )2, and -N(R d )-S(O)2-R d and optionally substituted with one or more groups independently selected from the group consisting of Each R d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carbocyclyl, and carbocyclyl (C 1-3 is selected from the group consisting of aryl, arylalkyl, R 4 , H, C 1-6 Alkyl, or -C(=O)-C 1-6 is alkyl, R 5 is H or C 1-6 It is an alkyl.

[0183] Compounds of formula II can be synthesized by methods known in the art, for example, methods described in U.S. Patent Publication No. 2018 / 0086720, the synthetic methods of which are incorporated by reference.

[0184] In some embodiments, the small molecule BRG1 and / or BRM inhibitor is a compound having the structure of formula III, or a pharma- ceutically acceptable salt thereof:

[0185] [ka]

[0186] In the formula, R 6 is halo, e.g., fluoro or chloro; R 7 is hydrogen, an optionally substituted amino, or an optionally substituted C 1-6 is alkyl, R 8 is an arbitrarily substituted C 6-10 Aryl or optionally substituted C 2-9 It is heteroaryl.

[0187] In some embodiments, the small molecule BRG1 and / or BRM inhibitor is a compound having the structure of any one of compounds 1-16, or a pharma- ceutically acceptable salt thereof.

[0188] [ka]

[0189] In some embodiments, the small molecule compound or a pharma- ceutically acceptable salt thereof is a degradant. In some embodiments, the degradant is a compound having the structure of formula IV: ALB Formula IV wherein A is a binding moiety for BRG1 and / or BRM, L is a linker, and B is a degradation moiety. In some embodiments, the degradation moiety is a ubiquitin ligase moiety. In some embodiments, the ubiquitin ligase binding moiety comprises a cereblon ligand, an IAP (inhibitor of apoptosis) ligand, mouse double minute 2 homolog (MDM2), a hydrophobic tag, or a von Hippel-Lindau ligand, or a derivative or analog thereof.

[0190] In some embodiments, A is a BRG1 binding moiety. In some embodiments, A is a BRM binding moiety. In some embodiments, A comprises the structure of any one of formulas I-III, or any one of compounds 1-16.

[0191] In some embodiments, the hydrophobic tag comprises diphenylmethane, adamantine, or tri-Boc arginine, i.e., the hydrophobic tag comprises the following structure:

[0192] [ka]

[0193] In some embodiments, the ubiquitin ligase binding moiety has the structure of Formula A, or a pharma- ceutically acceptable salt thereof:

[0194] [ka]

[0195] In the formula, X 1 is CH2, O, S, or NR 1 and R 1 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; X 2 is C=O, CH2, or

[0196] [ka]

[0197] and R 3 and R 4 is independently H, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl; m is 0, 1, 2, 3, or 4; and each R 2 are independently selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 It is aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino.

[0198] In some embodiments, the ubiquitin ligase binding moiety comprises the structure:

[0199] [ka]

[0200] or a derivative or analog thereof, or a pharma- ceutically acceptable salt thereof. In some embodiments, the ubiquitin ligase binding moiety comprises the structure of Formula B, or a pharma- ceutically acceptable salt thereof:

[0201] [ka]

[0202] In the formula, each R 4 , R 4’ , and R 7 are independently H, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl; R 5 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 aryl, R 6 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 aryl, n is 0, 1, 2, 3, or 4, and each R 8 are independently selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino, and each R 9 and R 10 are independently H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C 10 aryl, R 4’ or R 5 includes a bond to the linker.

[0203] In some embodiments, the ubiquitin ligase binding moiety comprises the structure:

[0204] [ka]

[0205] or a derivative or analog thereof, or a pharma- ceutically acceptable salt thereof. In some embodiments, the ubiquitin ligase binding moiety has the structure of Formula C, or a pharma- ceutically acceptable salt thereof:

[0206] [ka]

[0207] In the formula, each R 11 , R 13 , and R 15 are independently H, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl; R 12 is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 aryl, R 14 is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 aryl, p is 0, 1, 2, 3, or 4, and each R 16 are independently selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; q is 0, 1, 2, 3, or 4; and each R 17 are independently selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 It is aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino.

[0208] In some embodiments, the ubiquitin ligase binding moiety comprises the structure:

[0209] [ka]

[0210] or a derivative or analog thereof, or a pharma- ceutically acceptable salt thereof. In some embodiments, the ubiquitin ligase binding moiety has the structure of Formula D, or a pharma- ceutically acceptable salt thereof:

[0211] [ka]

[0212] In the formula, each R 18 and R 19 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl C3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 aryl, r1 is 0, 1, 2, 3, or 4, and each R 20 are independently selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; r2 is 0, 1, 2, 3, or 4; and each R 21 are independently selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 It is aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino.

[0213] In some embodiments, the ubiquitin ligase binding moiety comprises the structure:

[0214] [ka]

[0215] or a derivative or analog thereof, or a pharma- ceutically acceptable salt thereof. In some embodiments, the linker has the structure of Formula V: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D)-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 Formula V In the formula, A 1 is the bond between the linker and A, A 2 is the bond between B and the linker, and B 1 , B 2 , B 3 , and B 4 are each independently an optionally substituted C1-C2 alkyl, an optionally substituted C1-C3 heteroalkyl, O, S, S(O) 2、 and N.R. N Selected from R N is hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 2-6 Heterocyclyl, optionally substituted C 6-12 Aryl, or optionally substituted C 1-7 Heteroalkyl, C 1 and C 2are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, I, j, and k are each independently 0 or 1; D is an optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, optionally substituted C 2-10 Alkynyl, optionally substituted C 2-6 Heterocyclyl, optionally substituted C 6-12 Aryl, optionally substituted C2-C 10 Polyethylene glycol, or any substituted C 1-10 Heteroalkyl, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 is a chemical bond that connects

[0216] In some embodiments, D is an optionally substituted C-C 10 In some embodiments, C is polyethylene glycol. 1 and C 2 Each is independently carbonyl or sulfonyl. In some embodiments, B 1 , B 2 , B 3 , and B 4 are each independently an optionally substituted C1-C2 alkyl, an optionally substituted C1-C3 heteroalkyl, O, S, S(O)2, and NR N Selected from R N is hydrogen or an optionally substituted C 1-4 In some embodiments, B is alkyl. 1 , B 2 , B 3 , and B 4are each independently selected from optionally substituted C1-C2 alkyl or optionally substituted C1-C3 heteroalkyl. In some embodiments, j is 0. In some embodiments, k is 0. In some embodiments, j and k are each independently 0. In some embodiments, f, g, h, and i are each independently 1.

[0217] In some embodiments, the linker of formula V has the structure of formula Va:

[0218] [ka]

[0219] In the formula, A 1 is the bond between the linker and A, and A 2 is the bond between B and the linker. In some embodiments, D is optionally substituted C 1-10 In some embodiments, C 1 and C 2 Each is independently carbonyl. In some embodiments, B 1 , B 2 , B 3 , and B 4 are each independently an optionally substituted C1-C2 alkyl, an optionally substituted C1-C3 heteroalkyl, O, S, S(O)2, and NR N Selected from R N is hydrogen or an optionally substituted C 1-4 In some embodiments, B is alkyl. 1 , B 2 , B 3 , and B 4 each independently represents an optionally substituted C1-C2 alkyl, O, S, S(O)2, and NR N Selected from R N is hydrogen or an optionally substituted C 1-4 In some embodiments, B is alkyl. 1 and B. 4Each independently is an optionally substituted C1-C2 alkyl. In some embodiments, B 1 and B. 4 Each is independently C alkyl. In some embodiments, B 2 and B. 4 are each independently NR N and R N is hydrogen or an optionally substituted C 1-4 In some embodiments, B is alkyl. 2 and B. 4 In some embodiments, f, g, h, I, j, and k are each independently 1.

[0220] In some embodiments, the linker of formula V has the structure of formula Vb:

[0221] [ka]

[0222] In the formula, A 1 is the bond between the linker and A, and A 2 is the bond between B and the linker. Preferably, the compound used in the methods disclosed herein has the structure:

[0223] [ka]

[0224] or a pharma- ceutically acceptable salt thereof. More preferably, the compounds used in the methods disclosed herein have the structure:

[0225] [ka]

[0226] or a pharma- ceutically acceptable salt thereof. Combination preparations and their uses Agents that reduce the level and / or activity of BRG1 and / or BRM can be combined with one or more therapeutic agents. In particular, the therapeutic agents can be those that treat or prophylactically treat any of the cancers described herein.

[0227] Combination therapy The agent that reduces the level and / or activity of BRG1 and / or BRM can be used alone or in combination with additional therapeutic agents, such as other agents that treat cancer or related symptoms, or in combination with other types of treatments to treat cancer. In combination treatment, the dosage of one or more of the therapeutic compounds can be reduced from the standard dosage when administered alone. For example, dosage can be empirically determined from drug combinations and permutations, or estimated by isobologram analysis (e.g., Black et al., Neurology 65:S3-S6, 2005). In this case, the dosage of the compounds in combination is that which produces a therapeutic effect.

[0228] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic drug or other chemical useful in the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methyl hydrazine derivatives, adrenal cortical suppressants, corticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide, alkyl sulfonates such as busulfan, improsulfan, and piposulfan, aziridines such as benzodopa, carboquone, meturedopa, and uredopa, ethylenimines and methylameramines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine, acetogenins (specifically bullatacin and bullatacinone), camptothecins (including the synthetic analog topotecan), bryostatin, kallistatin, CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bezelesin), chlosporins, cyclosporins, and cyclosporins. Cryptophycins (specifically cryptophycin 1 and cryptophycin 8), dolastatins, duocarmycins (including the synthetic analogs KW-2189 and CB1-TM1), erytherobin, pancratistatin, sarcodictyin, spongistatin, nitrogen mustards such as chlorambucil, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trofosfamide, uracil mustard, nitrosoureas such as camrustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine, antibiotics such asEnediyne antibiotics (e.g., the calicheamicins, specifically calicheamicin gamma II and calicheamicin omega II (see, e.g., Agnew, Chem. Intl. Ed Engl. Ed Engl. 33:183-186 (1994)); including dynemicin A; dynemicins; bisphosphonates such as clodronate; esperamicins; and neocarzinostatin chromophore and related enediyne antibiotic chromophores), aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, doxorubicin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, Adriamycin® (doxorubicin, including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, maltose ... Anti-metabolites such as seromycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, methotrexate, and 5-fluorouracil (5-FU); denopterin, methotrexate, pteropterin, trimetrexor folic acid analogues such as purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; aminoglutethimide, mitotane,Anti-adrenal agents such as trilostane; folic acid replacement fluids such as floric acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; maytansinoids such as lonidynin, maytansine and ansamitocin; mitoguazone, mitoxantrone, mopidanmol, nitraelin, pentostatin; fenameth; pirarubicin; rosoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.), razoxane; rhizoxin; schizofiran; spirogermanium; tenuazonic acid; triazicon; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veraculin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids such as Taxol® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABraxane®, a chromophore-free, albumin engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and Taxotere® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; Gemzar® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; cisplatin, oxaliplatin,and platinum coordination complexes such as carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitors RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharma- ceutically acceptable salts, acids, or derivatives of any of the above. Two or more chemotherapeutic agents may be used in a cocktail administered in combination with a first therapeutic agent described herein. Suitable dosing regimens for combination chemotherapy are known in the art and are described, for example, in Saltz et al. (1999) Proc ASCO 18:233a and Douillard et al. (2000) Lancet 355:1041-7.

[0229] In some embodiments, the second therapeutic agent is a therapeutic agent that is a biologic, such as a cytokine (e.g., an interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments, the biologic is an anti-VEGF agent, e.g., an anti-angiogenic agent, such as bevacizumab (Avastin®). In some embodiments, the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, fully human antibody, Fc fusion protein, or functional fragments thereof) that stimulates a target to stimulate an anti-cancer response or antagonizes an antigen important to the cancer. Such agents include Rituxan (rituximab), Zenapax (daclizumab), Simulect (basiliximab), Synagis (palivizumab), Remicade (infliximab), Herceptin (trastuzumab), Mylotarg (gemtuzumab ozogamicin), Cambus (alemtuzumab), Zevalin (ibritumomab tiuxetan), Humira (adalimumab), Xolair (omalizumab), Bexar (tositumomab-I-131), Raptiva (efalizumab), Erbitux (cetuximab), Avastin (bevacizumab), Tysabri (natalizumab), and Actemra (tositumomab). (Cilizumab), Vectibix (panitumumab), Lucentis (ranibizumab), Soliris (eculizumab), Cimzia (certolizumab pegol), Simponi (golimumab), Ilaris (canakinumab), Stelara (ustekinumab), Arzera (ofatumumab), Prolia (denosumab), Numax (motavizumab), ABThrax (raxibacumab), Benlysta (belimumab), Yervoy (ipilimumab), Adcetris (brentuximab vedotin), Perjeta (pertuzumab), Kadcyla (trastuzumab emtansine), and Gazyva (obinutuzumab). Also included are antibody-drug conjugates.

[0230] The second agent can be a treatment that is a non-drug treatment, for example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia, and / or surgical removal of tumor tissue. The second agent can be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody can be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a ligand of the checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody, such as ipilimumab / Yervoy or tremelimumab). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab / Opdivo®, pembrolizumab / Keytruda®, pidilizumab / CT-011). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A / RG7446, MEDI4736, MSB0010718C, BMS 936559). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2 / Ig fusion protein such as AMP 224). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family of ligands, or combinations thereof.

[0231] In some embodiments, the agent that reduces the level and / or activity of BRG1 and / or BRM is used in combination with another anti-cancer therapy (such as surgery), a MEK inhibitor, and / or a PKC inhibitor, or a combination thereof. For example, in some embodiments, the method further comprises performing surgery before, after, or simultaneously with administration of the agent that reduces the level and / or activity of BRG1 and / or BRM. In some embodiments, the method further comprises administering a MEK inhibitor (e.g., selumetinib, binimetinib, or tametinib) and / or a PKC inhibitor (e.g., sotrastaurin or IDE196) before, after, or simultaneously with administration of the agent that reduces the level and / or activity of BRG1 and / or BRM.

[0232] In any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially, in any order. The first therapeutic agent may be administered before, immediately before, or after the second therapeutic agent, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7 days, 1-14 days, 1-21 days, or 1-30 days.

[0233] Pharmaceutical Compositions The compounds described herein can be formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.The pharmaceutical composition typically includes an active agent described herein and a physiologically acceptable excipient (e.g., a pharma-ceutical acceptable excipient).The formulation principles of the compounds disclosed herein can be, for example, those described in WO2020 / 160180, the disclosure of which is incorporated herein by reference in its entirety.

[0234] The compound of the present invention can be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, by patch, pump, or transdermal administration, and the pharmaceutical composition is formulated accordingly.Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary, intrathecal, rectal, and topical administration modes.Parenteral administration can be by continuous infusion over a selected period of time.Preferably, the compound is administered orally.

[0235] Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in detail in Remington: The Science and Practice of Pharmacy, 21, a reference text well known in the art. st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), and in the USP / NF (United States Pharmacopeia and National Formulary).

[0236] Unit dosage form The compounds described herein may be formulated in a unit dosage form (eg, a capsule) for oral administration.

[0237] The unit dosage form may contain suitable pharmaceutical carriers and excipients as described in the pharmaceutical composition section. The excipients may include, for example, anti-adhesive agents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (coloring agents), emollients, emulsifiers, fillers (diluents), film-forming or coating agents, flavoring agents, flavoring agents, glidants (glidants), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water for hydration. The unit dosage form may contain one or more of fillers, disintegrants, wetting agents, glidants, lubricants, and capsule shells.

[0238] In some examples, the bulking agent may be 70-90% (w / w) of the unit dosage form. The bulking agent may be microcrystalline cellulose, mannitol, or a combination thereof. In some examples, the disintegrant may be 4-6% (w / w) of the unit dosage form. The disintegrant may be croscarmellose sodium.

[0239] In some examples, the wetting agent may be 0.5-1.5% (w / w) of the unit dosage form. The wetting agent may be sodium lauryl sulfate. In some examples, the lubricant may be 1.5-2.5% (w / w) of the unit dosage form. The lubricant may be colloidal silicon dioxide.

[0240] In some examples, the lubricant may be 0.4-0.6% (w / w) of the unit dosage form. The lubricant may be magnesium stearate. In some examples, the capsule shell is made of a polymer shell. The polymer shell can be made of hypromellose and titanium dioxide.

[0241] The compounds described herein can be formulated into a unit dosage form (e.g., a capsule) for oral administration, as set forth in Table 1. The APIs in Table 1 are compounds of the following structure:

[0242] [ka]

[0243] [Table 1]

[0244] The composition of the Swedish Orange hypromellose capsule shell is set forth in Table 2.

[0245] [Table 2]

[0246] The composition of the blue-green hypromellose capsule shell is set forth in Table 3.

[0247] [Table 3] EXAMPLES

[0248] An ascending dose escalation clinical trial of the compounds set forth below will be conducted, which is primarily intended to evaluate the safety and tolerability of the compounds set forth below when administered orally to subjects with advanced hematological malignancies, specifically, relapsed or refractory acute myeloid leukemia (R / R AML) or myelodysplastic syndromes (MDS).

[0249] [ka]

[0250] In this ongoing study, clinically significant signs and symptoms associated with blood cell differentiation were reported in one of 21 subjects with acute myeloid leukemia treated with the compound identified above, which occurred approximately 7-14 days after treatment with the compound identified above.

[0251] Other embodiments While the invention has been described in relation to specific embodiments thereof, it will be understood that the invention is capable of further modifications, and this application is intended to cover any variations, uses, or adaptations of the invention which generally follow the principles of the invention and include such departures from the present disclosure which are within known or customary practice within the art to which the invention pertains, as may be applied to the essential features described above and fall within the scope of the appended claims.

[0252] Other embodiments are within the claims.

Claims

1. A method of treating a subject having clinically significant signs and symptoms associated with blood cell differentiation and who has been treated with an agent that reduces the level and / or activity of BRG1 and / or BRM, comprising administering to the subject an effective amount of a corticosteroid, hydroxyurea, or furosemide, or subjecting the subject to leukapheresis.

2. A method of treating a subject having differentiation syndrome and being treated with an agent that reduces the level and / or activity of BRG1 and / or BRM, comprising administering to the subject an effective amount of a corticosteroid, hydroxyurea, or furosemide, or subjecting the subject to leukapheresis.

3. A method of treating a subject suspected of having differentiation syndrome and who has been treated with an agent that reduces the level and / or activity of BRG1 and / or BRM, comprising administering to the subject an effective amount of a corticosteroid, hydroxyurea, or furosemide, or subjecting the subject to leukapheresis.

4. The method of any one of claims 1 to 3, wherein the subject is treated with an agent that reduces the level and / or activity of BRG1 and / or BRM in an amount effective against leukemia.

5. 5. The method of claim 4, wherein the leukemia is acute myeloid leukemia.

6. The method of any one of claims 1 to 3, wherein the subject is treated with an effective amount of an agent that reduces the level and / or activity of BRG1 and / or BRM for myelodysplastic syndrome.

7. The method of any one of claims 1 to 5, wherein the method further comprises administering an agent that reduces the level and / or activity of said BRG1 and / or BRM.

8. A method of treating a subject having leukemia or myelodysplastic syndrome, comprising administering an effective amount of an agent that reduces the level and / or activity of BRG1 and / or BRM, and if the subject has clinically significant signs and symptoms associated with blood cell differentiation, administering to the subject an effective amount of a corticosteroid, hydroxyurea, or furosemide, or subjecting the subject to leukapheresis.

9. A method of treating a subject having leukemia or myelodysplastic syndrome, comprising administering an effective amount of an agent that reduces the level and / or activity of BRG1 and / or BRM, and if the subject has differentiation syndrome, administering to the subject an effective amount of a corticosteroid, hydroxyurea, or furosemide, or subjecting the subject to leukapheresis.

10. A method of treating a subject having leukemia or myelodysplastic syndrome, comprising administering an effective amount of an agent that reduces the level and / or activity of BRG1 and / or BRM, and if the subject is suspected of having differentiation syndrome, administering to the subject an effective amount of a corticosteroid, hydroxyurea, or furosemide, or subjecting the subject to leukapheresis.

11. The method of any one of claims 8 to 10, wherein the subject has leukemia.

12. 12. The method of claim 11, wherein the leukemia is acute myeloid leukemia.

13. The method of any one of claims 8 to 10, wherein the subject has a myelodysplastic syndrome.

14. 14. The method of any one of claims 1-13, wherein the subject exhibits one or more of the following symptoms: fever of unknown origin, skin rash, hypoxia, impaired respiratory function, interstitial lung infiltrates, pleural and / or pericardial effusion, weight gain, renal failure, difficulty breathing, clinical deterioration, fluid in or around the lungs, fluid around the heart, swelling in the legs, increased bilirubin, and increased liver enzymes.

15. The method of any one of claims 1 to 14, wherein the blood sample from the subject comprises an elevated absolute neutrophil count (ANC) and / or an elevated platelet count.

16. The method of any one of claims 1 to 15, wherein the subject is administered an effective amount of a corticosteroid.

17. 17. The method of claim 16, wherein the corticosteroid is administered systemically.

18. 17. The method of claim 16, wherein the corticosteroid is administered orally or by injection.

19. 19. The method of any one of claims 16 to 18, wherein the subject is administered a high-dose regimen of corticosteroids.

20. 20. The method of any one of claims 16 to 19, wherein the subject is administered the corticosteroid for at least 3 days.

21. 21. The method of any one of claims 16 to 20, wherein the corticosteroid is dexamethasone, ethamethazoneb, hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, triamcinolone, a pharma- ceutically acceptable salt thereof, or a combination thereof.

22. 22. The method of any one of claims 16 to 21, wherein administration of the agent that reduces the level and / or activity of BRG1 and / or BRM is discontinued if clinically significant signs and symptoms associated with blood cell differentiation or symptoms of the differentiation syndrome persist for at least 48 hours after initiation of corticosteroid administration.

23. 22. The method of any one of claims 16 to 21, wherein administration of the agent that reduces BRG1 and / or BRM levels and / or activity is discontinued if clinically significant signs and symptoms associated with blood cell differentiation or symptoms of the differentiation syndrome persist for at least 3 days after initiation of corticosteroid administration.

24. The method of any one of claims 1 to 23, wherein the subject has symptoms of non-infectious leukocytosis.

25. 25. The method of any one of claims 1 to 24, wherein the method comprises administering to the subject an effective amount of hydroxyurea.

26. 26. The method of claim 25, wherein an effective amount of hydroxyurea is administered to the subject until non-infectious leukocytosis improves or resolves.

27. The method of any one of claims 1 to 26, wherein the method comprises subjecting the subject to leukapheresis.

28. The method of any one of claims 1 to 27, wherein the subject experiences hypervolemia.

29. 29. The method of claim 28, wherein an effective amount of furosemide is administered to the subject.

30. The agent that reduces the level and / or activity of BRG1 and / or BRM is a compound of the following structure: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof.

31. The agent that reduces the level and / or activity of BRG1 and / or BRM is a compound of the following structure: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

32. The method of any one of claims 1 to 31, wherein the agent that reduces the level and / or activity of BRG1 and / or BRM is administered orally.

33. The method of any one of claims 1 to 32, wherein the agent that reduces the level and / or activity of BRG1 and / or BRM is administered in a unit dosage form selected from the group consisting of a capsule or a tablet.

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