Compounds and uses thereof
Inventors
Wilson, Kevin J. • Schiller, Shawn E. R. • NEGRETTI, Solymar
Assignees
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Publication Number
US-12441726-B2
Publication Date
2025-10-14
Expiration Date
Abstract
The present disclosure features compounds useful for the treatment of BAF complex-related disorders.
Core Innovation
The disclosure provides compounds having the structure of Formula I and Formula Ia, including pharmaceutically acceptable salts. The compounds are defined by variable structural elements including A, m, n, o, X, X′, B, L, C, and substituents R1, R2/R3, R4, R5, and R6, with X selected from O, CH2, or NR7, and X′ selected from N, CH, or CRX, wherein RX is a halogen.
The compounds are described as BRG1/BRM (BAF complex) modulators. The disclosure includes pharmaceutical compositions and methods to decrease BAF complex activity in cells, including cancer cells, using the disclosed compounds, with BRG1 level/activity reduction and BRM level/activity reduction.
The disclosure also targets disorders related to BRG1/BRM and BRG1 loss of function mutation-related disorders. Methods of treating cancer are described, including cancer type lists and endpoints such as tumor size, tumor growth rate, metastases, metastatic colonization, tumor recurrence, progression-free survival, and overall survival.
Claims Coverage
The provided claim information centers on a structurally defined Formula I/Formula Ia compound scaffold and includes a pharmaceutically acceptable salt; the therapeutic scope also includes cancer treatment. The core coverage comprises six inventive feature groupings spanning the scaffold, ring selection, linker options, substituent pattern, salt coverage, and treatment method.
Structurally defined Formula I compound scaffold with variable ring and substituent pattern
A compound having the structure defined by A, m, n, o, X, X′, B, L, C, and substituents R1, R2/R3, R4, R5, and R6, with X selected from O, CH2, or NR7 and X′ selected from N, CH, or CRX wherein RX is a halogen, and including pharmaceutically acceptable salt thereof.
Heteroarylene ring B selection
B is an optionally substituted 6-membered monocyclic heteroarylene or an optionally substituted 9- or 10-membered bicyclic heteroarylene.
Linker L selection across bond, chain, and ring classes
L is a covalent bond or optionally substituted C1-C3 alkylene, C2 alkynylene, optionally substituted C2 alkenylene, optionally substituted C2-C3 heteroalkylene, optionally substituted C3-C5 cycloalkylene, or optionally substituted 4- to 10-membered heterocyclylene.
Ring system C selection
C is optionally substituted cycloalkyl, aryl, heteroaryl, or heterocyclyl within the defined size ranges.
Substituent selection for R4, R5, and R6
R4 is cyano, fluoro, hydroxy, or —CH2OH, and R5 and R6 are C1-C3 alkyl optionally substituted with one through seven fluoro groups.
Cancer treatment by administering the compound
A method for treating cancer in a subject by administering an effective amount of a compound described in claim 1.
The claim coverage is directed to a structurally defined Formula I/Formula Ia compound scaffold with defined heteroatom selections, ring system choices, linker options, and substituent constraints, together with pharmaceutically acceptable salts. The claim set also includes a cancer-treatment method using the claim 1 compound.
Stated Advantages
Modulating BRG1/BRM activity in mammals for therapeutic effects in cancer contexts.
Treating BRG1 loss-of-function mutation-related cancers.
Reported inhibition of BRG1/BRM activity and cell proliferation.
Dose-dependent tumor growth inhibition/regression and tolerability in vivo xenograft tumor models.
Provides broad pharmaceutical and therapeutic scope for Formula I/Formula Ia compounds as BRG1/BRM (BAF complex) modulators.
Decreases BAF complex activity in cells, including cancer cells, with BRG1 and BRM level/activity reduction.
Induces apoptosis as described outcomes of BRG1/BRM inhibition.
Treats BAF complex-related disorders and BRG1 loss of function mutation-related disorders.
Includes cancer treatment with endpoints such as tumor size, tumor growth rate, metastases, tumor recurrence, progression-free survival, and overall survival.
Describes combination therapy.
Documented Applications
Treating BRG1 loss-of-function mutation-related cancers by inhibiting BRG1/BRM in mammals.
Therapeutic outcome evaluation including tumor size, tumor growth, metastasis, survival, and mortality.
Characterization and biological evaluation of BRG1/BRM ATPase inhibitors, including in vitro ATPase activity and cell-growth inhibition studies across diverse cancer cell lines.
In vivo xenograft tumor model results for Compound C, including dose-dependent tumor growth inhibition/regression and tolerability.
Decreasing BAF complex activity in cells, including cancer cells.
Treating BAF complex-related disorders, especially cancer.
Treating BRG1 loss of function mutation-related disorders.
Cancer treatment in a subject with endpoints including tumor size, tumor growth rate, metastases, tumor recurrence, progression-free survival, and overall survival.
Inducing apoptosis in the context of BRG1/BRM inhibition.
Combination therapy in cancer treatment settings.
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