Abstract C011: Discovery of novel SMARCA2 small molecule inhibitors with best-in-class potency and selectivity for the treatment of SMARCA4-mutant cancers

Abstract Patients with homozygous SMARCA4 loss of function (LOF) aberrations represent a high unmet medical need. Occurring in ∼5% of non-small-cell-lung-cancer (NSCLC) patients, SMARCA4 deficiency represents a distinct molecular subset that is mutually exclusive with most other oncogenic drivers and associated with resistance to radiotherapy, chemotherapy and PD-L1 treatment. SMARCA4 LOF aberrations can co-occur with KRAS-G12C oncogenic mutations in NSCLC, leading to resistance to KRAS targeted therapies. Interestingly, loss of SMARCA4 activity results in a complete dependency on SMARCA2, creating a unique synthetically lethal relationship that has been validated by both genetic and pharmacological approaches. Though developing selective SMARCA2 inhibitors has been challenging due its similarity with SMARCA4, selectivity over SMARCA4 is essential. Multiple Phase 1 clinical trials exploring the SMARCA4/2 dual inhibitor FHD-286 in different indications were discontinued, flagging safety concerns. Thus, there is a clear need to develop a highly potent & selective SMARCA2 small molecule inhibitor to fully unlock the therapeutic potential of this target. At Onco3R Therapeutics, our patient centric approach, integrating deep translational science with rational, structure-based and AI-augmented drug design, has led to the identification of novel SMARCA2 selective small molecule inhibitor series with a best-in-class potency and selectivity profile. Our lead series inhibits SMARCA2 activity with sub-nanomolar potencies while exhibiting over 35-fold selectivity against SMARCA4 in a KRT80 qRT-PCR assay using SMARCA2 or SMARCA4 isogenic cells. Anti-proliferative activity was confirmed in SMARCA4 deficient SK-MEL5 cells. Moreover, Onco3R series exhibit favourable in vitro ADME-safety properties and good PK profiles, enabling robust in vivo characterization. Oral dosing achieved sufficient target coverage to lead to tumor regression in a SMARCA4 deficient RERF-LC-A1 based cell line derived xenograft (CDX) mouse model. Here, we identified unique SMARCA2 selective inhibitor series with a best-in-class potency and selectivity profile. Thorough characterization and optimization efforts are ongoing to identify clinical development candidates with the ultimate goal of achieving greater efficacy along with enhanced safety, providing meaningful benefits to patients diagnosed with SMARCA4 deficient cancer. Citation Format: Lijs Beke, Sandrine Grosse, Shaun Martin, Godelieve Lammens, Pieter Peeters, Bart Stoops, Sandrine Vendeville, Stéphane de Cesco, Pierre Raboisson, Sara Musch, David Moreno Delgado, Line Oste, Francois Gonzalvez. Discovery of novel SMARCA2 small molecule inhibitors with best-in-class potency and selectivity for the treatment of SMARCA4-mutant cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C011.