Abstract 7019: Identification of first-in-class paralog selective SMARCA4 degraders for treatment of hematological and prostate malignancies

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 regulates important cellular functions including transcription, DNA recombination, DNA repair and chromosome decatenation during mitosis. SMARCA4 is frequently overexpressed in several types of cancers. Overexpression has been linked to increased proliferation and survival, as well as aggressive tumors and poor prognosis. SMARCA4 knockdown in these tumors lead to inhibition of proliferation and increased sensitivity to known chemotherapeutic agents, supporting the validity of targeting SMARCA4. In addition, PTEN and SMARCA4 appear to share synthetic lethality relationship based on reported in vitro and in vivo knockdown studies. Considering this well-established biological rationale, selective degradation of SMARCA4 should offer significant clinical benefit in multiple disease settings. Here, we report first-in-class SMARCA4 selective degraders that demonstrate distinct cellular phenotype. As part of the initial design plan, selective SMARCA2/4 Bromodomain inhibitors and specific ligands of several E3 ligases were chosen to arrive at different degrader designs. Several linkers and different exit vectors were considered to construct a variety of hetero-bifunctional degrader molecules. Our proprietary ternary complex modeling algorithm, ALMOND4 (ALgorithm for MOdeling Neosubstrate Degraders) helped in prioritizing the designs. Shortlisted compounds were synthesized and profiled in multiple cellular assays to understand their potential to degrade SMARCA4 selectively. These compounds exhibited very potent anti-proliferative activity in cell lines of hematological and prostate cancer origin (e.g. MV-4-11, VCaP, etc.) whereas no significant potency is observed in SMARCA4 mutant cell lines. Identified compounds have shown selective degradation of SMARCA4 over SMARCA2 in multiple cell lines. Few potent SMARCA4 selective degraders were optimized for pharmacokinetic properties and further evaluation of tolerability and efficacy in rodents is in progress. Citation Format: Chandrasekhar Abbineni, Kiran Aithal, Bilash Kuila, Sandeep Vitthal Dukare, Arya Desai, Megha Goyal, Khaji Abdul Rawoof, Gauri Rahul Petkar, 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, Susanta Samajdar, Murali Ramachandra. Identification of first-in-class paralog selective SMARCA4 degraders for treatment of hematological and prostate malignancies [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 7019.