HD-10991

HD-10991 is a selective small molecule inhibitor of SMARCA2 (also known as BRM), which is one of the two mutually exclusive catalytic ATPase subunits of the BAF (SWI/SNF) chromatin remodeling complex. Developed by Hyundai Pharm, HD-10991 is designed to exploit synthetic lethality in cancers harboring mutations in SMARCA4 (BRG1), the other catalytic subunit of the BAF complex. In SMARCA4-deficient cells, the complex becomes dependent on SMARCA2 for survival. HD-10991 binds to the ATPase domain of SMARCA2 with single-digit nanomolar potency and exhibits over 30-fold selectivity over SMARCA4. Preclinical data indicate that the compound has favorable pharmacokinetic properties for oral administration and demonstrates significant anti-tumor efficacy, including tumor regression, in SMARCA4-mutant xenograft models of non-small cell lung cancer (NSCLC) and melanoma.