Abstract 6984: Discovery of selective SMARCA2 inhibitors for the treatments of SMARCA4 mutated cancers

Abstract BRM and BRG (SMARCA2/4) are two mutually exclusive catalytic ATPase subunits of the BAF complexes. SMARCA4 is frequently mutated in multiple cancers, including about 10% of non-small cell lung cancer (NSCLC). As a result, SMARCA4 deficient cancer cell becomes more dependent on its paralog, SMARCA2, for their survival. Consequently, a selective inhibitor targeting SMARCA2 is a potentially effective therapeutic option for SMARCA4-mutant cancers. We identified HD-10991 and HD-11030 as selective SMARCA2 inhibitors and evaluated their potency in SMARCA2 and SMARCA4 biochemical assays, as well as in Cell Titer-Glo assays using melanoma and NSCLC cell lines. HD-10991 and HD-11030 effectively inhibited SMARCA2 activity with single-digit nanomolar potency by binding to the ATPase domain. Both compounds demonstrated excellent selectivity, showing over 30-fold greater potency against BRM compared to BRG1 in chromatin remodeling assays. HD-10991 and HD-11030 possess desirable drug-like properties for oral administration, including favorable physicochemical characteristics and pharmacokinetic profiles. Systemic exposure through oral administration resulted in dose-dependent anti-tumor effects, consistently leading to tumor growth arrest and regression in SMARCA4-mutant xenograft models, such as SK-MEL-5 and A549 CDX models. Additional in vitro and in vivo studies in SMARCA4-mutant cell lines are ongoing to support the further development of these compounds. These findings, highlighting the anti-tumor efficacy and promising drug-like properties of HD-10991 and HD-11030, underscore their potential as candidates for preclinical studies aimed at therapeutic intervention for patients with SMARCA4-mutant cancers. Citation Format: Seong Heon Kim, Hyuntae Kim, Sukho Lee, Minou Choi, Jong Woo Park, Hyosun Choi, Goeun Yang, Daehoon Kim, Doo-Young Kim, Sunhee Lee, Min Ah Park. Discovery of selective SMARCA2 inhibitors for the treatments of SMARCA4 mutated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6984.