Discovery and characterization of once in a month intravenous and orally bioavailable SMARCA2 degraders for treating SMARCA4 mutant cancers

The BAF (SWI/SNF) chromatin remodelling complex is a multi-subunit assembly that regulates chromatin accessibility via ATP-dependent nucleosome repositioning, thereby modulating transcription, DNA recombination & repair, and mitotic chromosome segregation. Its catalytic activity is mediated by two mutually exclusive ATPases, SMARCA2 (BRM) and SMARCA4 (BRG1). In SMARCA4-deficient tumors, oncogenic dependency shifts to the residual SMARCA2-containing SWI/SNF complex, establishing a synthetic lethal vulnerability. This dependency has been validated through genetic silencing studies, positioning SMARCA2 as a compelling therapeutic target in SMARCA4-mutant cancers. We report the identification and preclinical development of highly potent and selective SMARCA2 degraders based on rational design by optimizing assemblies of SMARCA2/4 bromodomain binders, degron-linking moieties, and ligands for specific E3 ligases. Design prioritization was guided by our proprietary ternary complex modelling algorithm, ALMOND (ALgorithm for MOdeling Neosubstrate Degraders). Selected compounds were synthesized and evaluated across multiple cellular assays to assess mechanistic and functional outcomes. Several compounds demonstrated potent and selective SMARCA2 degradation, eliciting distinct phenotypic responses in a panel of SMARCA4-mutant cell lines. The lead IV compound demonstrated robust anti-tumor efficacy in multiple SMARCA4 mutant xenograft models with confirmed target degradation, at well tolerated doses. IND application was accepted by USFDA for this compound. Formulation efforts helped in identification of long-acting IV formulation which demonstrated significant efficacy following once in 4 weeks administration. Subsequent ADME optimization yielded compounds with favourable oral bioavailability across tested species. Furthermore, the lead degrader exhibited robust antitumor efficacy in multiple SMARCA4-deficient CDX models at well-tolerated doses. Repeat-dose tolerability studies in non-rodent species are ongoing to support candidate nomination by Q4 2025.