Abstract C025: Identification of an orally bio-available SMARCA2 selective degrader for treatment of SMARCA4 mutant cancers

Abstract The BAF (SWI/SNF) chromatin remodelling complex comprises two mutually exclusive ATP-dependent helicase subunits, SMARCA2 (BRM) and SMARCA4 (BRG1), which regulate chromatin architecture by mobilizing and repositioning nucleosomes on DNA. This activity is critical for various genomic functions, including transcriptional regulation, DNA recombination and repair, and mitotic chromosome segregation. Loss-of-function mutations or silencing of SMARCA4 are frequently observed in multiple cancer types, where tumorigenesis becomes dependent on the residual SMARCA2-containing SWI/SNF complexes, thereby creating a synthetic lethal vulnerability. This report describes the identification and characterization of orally bioavailable SMARCA2 degrader with good potency and selectivity over SMARCA4. SAR comprised of a range of SMARCA2/4 Bromodomain binders, exit vectors, degron connecting linkers and ligands of specific E3 ligases. Selected designs were synthesized and profiled in multiple cellular assays to understand the mechanistic and functional trends. Several compounds that potently and selectively degrade SMARCA2 were identified with a distinct phenotype in a panel of SMARCA4 mutant cell lines. ADME optimization efforts resulted in the development of compounds exhibiting favorable oral bioavailability in both rodent and non-rodent species. The lead SMARCA2 degrader demonstrated potent antitumor activity, driven by efficient SMARCA2 degradation, in multiple SMARCA4-deficient cell line-derived xenograft (CDX) models at well-tolerated dose levels. Ongoing repeat-dose toxicology studies in non-rodent species aim to establish the tolerability profile of the lead compound to support candidate nomination. Citation Format: Bilash Kuila, Kiran Aithal, Sandeep Dukare, Charamanna KB, Khaji Abdul Rawoof, Prasath Kothandaraman, Nandish C, Madhu KL, Arya Desai, Dhaytadak Bhagwan Mahadeo, Gopinath CH, T Jagadeesh Kumar, Megha Goyal, Suraj Tgore, Leena Khare, Samiulla DS, Subhendu Mukherjee, Kavitha Nellore, Sanjeev Giri, Rajesh Eswarappa, Girish Daginakatte, Chandrasekhar Abbineni, Murali Ramachandra, Susanta Samajdar. Identification of an orally bio-available SMARCA2 selective degrader for 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 C025.