BRM/BRG1 inhibitors and uses thereof
Inventors
Anthony, Neville John • Vaswani, Rishi G. • Millan, David Simon • Schiller, Shawn E. R.
Assignees
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Publication Number
US-12509453-B2
Publication Date
2025-12-30
Expiration Date
Abstract
The compounds disclosed herein may be inhibitors of BRG1 (Brahma-related gene-1) and/or BRM (Brahma). The compounds or pharmaceutically acceptable salts thereof are useful for the treatment of disorders associated with an alteration in a BAF complex, e.g., a disorder associated with an alteration in one or both of the BRG1 and BRM proteins. Also disclosed are pharmaceutical compositions containing the compounds or pharmaceutically acceptable salts thereof and methods of their preparation and use.
Core Innovation
The invention relates to compounds having a defined chemical structure that includes a core scaffold identified as Formula I, with variable substituents including Y, R1–R8, Het, A, L, and B. The definition specifies that Y is N or CH, L is absent, and B is cyano or optionally substituted aryl, cycloalkyl, heterocyclyl, or heteroaryl groups, with additional limits placed on each of R1–R8 and Het. The compounds are also defined to include pharmaceutically acceptable salts.
The patent further defines alternative scaffolds corresponding to Formula II, Formula III, and Formula IV, including additional embodiment restrictions involving how groups B and other variables are selected and how substituents may be substituted. The alternative scaffold descriptions include stated constraints such as the absence of L and restrictions on substituent combinations. The document states that the disclosure includes specific enumerated compounds as examples.
The invention also includes pharmaceutical composition coverage comprising the compounds together with pharmaceutically acceptable excipients. In addition, the document states that the compounds are useful for disorders associated with altered BAF complex function, specifically targeting BRG1 (SMARCA4) and/or BRM (SMARCA2) in connection with SWI/SNF chromatin remodeling complex function. Example compounds are identified in an enumerated list (Table 1, compounds 1–47).
Claims Coverage
The independent claim coverage centers on a broad structurally defined compound genus with extensive substituent variability, explicit ring-forming limitations for R2 and R3, defined Het, A, L, and B options, and coverage of pharmaceutically acceptable salts. The independent claim material captures 2 inventive features: the Formula I structural scaffold with defined substituent rules, and pharmaceutically acceptable salt coverage.
Formula I compound scaffold with defined substituent rules
A compound having the structure of the defined scaffold, wherein Y is N or CH; L is absent; Het is a 5- or 6-membered heteroaryl; B is cyano, optionally substituted C6-C10 aryl, C6-C10 cycloalkyl, C2-C9 heterocyclyl, or C2-C9 heteroaryl; and each of R1–R9 and A are defined by the stated options and optional substitution limits, including the specified relationship constraints for R2 and R3 and the ring-formation option for R2 and R3.
Pharmaceutically acceptable salt coverage
The compound is defined as including a pharmaceutically acceptable salt thereof.
Independent claim coverage centers on the Formula I structural scaffold with L absent, with defined options for Y, R1–R8, Het, A, and B, including explicit constraints such as a 5- or 6-membered ring formation option involving R2 and R3. The claim additionally covers pharmaceutically acceptable salts of the defined compounds.
Stated Advantages
Reduction of tumor growth.
Reduction of tumor metastasis.
Reduction of cancer recurrence.
Increases in survival.
Increase in progression-free survival.
Reduction in tumor size and/or reduced tumor growth rate.
Increased tumor cell death.
Reduced metastases.
Increased survival.
Mention of progression-free survival.
Documented Applications
Treatment of BRG1 loss-of-function mutation-related cancers, including non-small cell lung cancer, colorectal cancer, melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, non-Hodgkin lymphoma, and small-cell lung cancer.
Treatment or utility by inhibiting or modulating the BAF complex via inhibiting BRG1 and/or BRM, including BRM/BRG1 dual inhibition and BRM-selective inhibition, with apoptosis induction described as related to the utility.
Treatment use cases for cancers listed in dependent-claim member summaries, including melanoma, hematologic cancer, prostate cancer, breast cancer, and bone cancer.
Disorder and viral infection scope, including Retroviridae and examples HIV, HBV, and HCV.
Treating BRG1 loss-of-function cancers using BRG1/BRM inhibitors.
Treatment method use case for melanoma, hematologic cancer, prostate cancer, breast cancer, or bone cancer by administering an effective amount of the compound of claim 1.
Pharmaceutical composition use and combination therapy context, including combination with chemotherapeutic agents and checkpoint inhibitors (e.g., CTLA-4, PD-1, PD-L1, PD-L2, LAG3, VISTA).
Inhibition of cancer cell proliferation by “Compound B” (Fig. 3).
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