Abstract 7024: Discovery of highly selective, potent and orally bio-available SMARCA2 degraders

Abstract The BAF (SWI/SNF) chromatin remodeling complex comprises of two mutually exclusive ATPases, SMARCA2 (BRM) and SMARCA4 (BRG1), that affect the mobilization and positioning of nucleosomes on DNA and thereby regulate important cellular functions including transcription, DNA recombination, DNA repair and chromosome decatenation during mitosis. Genetic silencing studies have established that the oncogenic activity of tumors lacking SMARCA4 is primarily driven by SMARCA2-containing residual SWI/SNF complex. Thus, targeting SMARCA2 in a SMARCA4 mutant setting is synthetically lethal. Considering this well-established biological rationale, selective targeting of SMARCA2 could be a precision oncology opportunity to meet an unmet medical need. Here, we report the identification and development of highly selective SMARCA2 degrader with oral bioavailability that have demonstrated robust efficacy in SMARCA4 mutant CDX models. SMARCA2 selective degraders were identified by optimizing an assembly of SMARCA2/4 Bromodomain binders, degron connecting linkers and several ligands of specific E3 ligases. Design prioritizations were done using a proprietary ternary complex modelling algorithm, ALMOND (ALgorithm for MOdeling Neosubstrate Degraders). Prioritized designs were synthesized and profiled in multiple cellular assays to understand the mechanistic and functional readouts. Several compounds that potently and selectively degrade SMARCA2 were identified with a distinct phenotype in a panel of SMARCA4 mutant cell lines. ADME optimization led to development of compounds with encouraging oral bioavailability in rodent as well as non-rodent species. Global proteomics indicated highly selective SMARCA2 downregulation in a SMARCA2/4 proficient cell line. Further, the identified degrader demonstrated robust efficacy supported by SMARCA2 degradation in multiple SMARCA4-mutant CDX models, at well-tolerated doses. Repeat dose tolerability profile of the lead compound in non-rodent species is ongoing towards candidate nomination. Citation Format: Chandrasekhar Abbineni, Kiran Aithal, Bilash Kuila, Sandeep Vitthal Dukare, Prasath Kothandaraman, Arya Desai, Megha Goyal, Khaji Abdul Rawoof, Dhaytadak Bhagwan Mahadeo, Gopinath CH, T Jagadeesh Kumar, Charamanna KB, Rahul B. Chavan, Nandish C, Suraj Tgore, Leena Khare, DS Samiulla, Subhendu Mukherjee, Thomas Antony, Kavitha Nellore, Sanjeev Giri, Rajesh Eswarappa, Girish Daginakatte, Murali Ramachandra, Susanta Samajdar. Discovery of highly selective, potent and orally bio-available SMARCA2 degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7024.