Selective degradation of SMARCA4 as a therapeutic strategy in SMARCA4 driven cancers

The BAF (SWI/SNF) chromatin remodelling complex regulates nucleosome positioning and DNA accessibility, influencing transcription, recombination, repair, and mitotic chromosome decatenation. It contains two mutually exclusive ATPases, SMARCA2 (BRM) and SMARCA4 (BRG1). SMARCA4 is frequently overexpressed in several cancers and is associated with aggressive phenotypes and poor prognosis. Genetic knockdown of SMARCA4 reduces proliferation and sensitizes tumors to chemotherapeutics, validating SMARCA4 as a therapeutic target. Synthetic lethality between SMARCA4 and PTEN further supports its clinical relevance. Here, we developed a first-in-class SMARCA4-selective degrader using hetero-bifunctional molecules that combine SMARCA2/4 bromodomain inhibitors with E3 ligase ligands. Design prioritization was guided by our proprietary ternary complex modelling algorithm, ALMOND (ALgorithm for MOdeling Neosubstrate Degraders). Multiple linker chemistries and exit vectors were explored based on rational designs which resulted in selective SMARCA4 degraders with good anti-proliferative activity in multiple cancer cell lines. Lead compound exhibited potent anti-proliferative effects in hematological and prostate cancer models, while SMARCA4-mutant cell lines showed minimal sensitivity, confirming target dependency. Preliminary tolerability and efficacy studies support the therapeutic potential of SMARCA4 degradation. These findings establish proof-of-concept for targeting SMARCA4 via targeted protein degradation as a novel strategy for treating SMARCA4-driven cancers with improved safety margin. Advanced in-vivo studies are in progress to complete candidate nomination by Q1 2026