Discovery of novel SMARCA2 small molecule inhibitors with best-in-class potency and selectivity for the treatment of SMARCA4-mutant cancers

Patients with homozygous loss-of-function (LOF) mutations in SMARCA4 constitute a molecularly distinct subgroup of non-small-cell lung cancer (NSCLC), encompassing approximately 5% of all patients. This subset is defined by its mutual exclusivity with other oncogenic drivers and demonstrates resistance to standard treatments, including radiotherapy, chemotherapy, and PD-L1 inhibitors. Notably, SMARCA4 LOF can co-occur with KRAS-G12C mutations, leading to resistance against KRAS-targeted therapies. Mechanistically, the loss of SMARCA4 function creates a synthetic lethal dependency on SMARCA2, a vulnerability that has been validated through both genetic and pharmacological approaches. However, the development of selective SMARCA2 inhibitors remains challenging due to the high sequence homology between SMARCA2 and SMARCA4-yet achieving selectivity is critical for clinical success. Previous clinical trials with a dual SMARCA4/2 inhibitor were discontinued due to safety concerns, highlighting the urgent need for potent and selective SMARCA2 inhibitors. Addressing this therapeutic gap could unlock the full potential of targeting SMARCA2 in SMARCA4-deficient cancers. At Onco3R Therapeutics, our patient-centric strategy-combining deep translational science with rational, structure-based and AI-augmented drug design-has led to the discovery of a novel series of SMARCA2-selective small molecule inhibitors with a best-in-class potency and selectivity profile. Lead compounds exhibited single digit to sub-nanomolar activity and over 30-fold selectivity for SMARCA2 versus SMARCA4, as demonstrated in a KRT80 qRT-PCR assay using SMARCA2/4 isogenic knockout cell lines. Notably, these lead compounds combined potent anti-proliferative effects in SMARCA4-deficient cells with favourable in vitro ADME characteristics, a supportive safety profile and pharmacokinetic properties suitable for in vivo evaluation. Following oral administration, the compounds achieved sustained target engagement and elicited pronounced anti-tumor activity in a SMARCA4-deficient RERF-LC-A1 CDX mouse model without evidence of SMARCA4-related body weight loss. These unique SMARCA2-selective lead compounds are currently further profiled as potential clinical candidate with the ultimate goal of delivering transformative efficacy and enhanced safety for patients with SMARCA4-deficient cancers.