Abstract A046: Identification of paralog selective degraders of SMARCA2 and SMARCA4 for treatment of various cancers

Abstract

Abstract Background: 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. 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 led to inhibition of proliferation and increased sensitivity to known chemotherapeutic agents, supporting the validity of targeting SMARCA4. Further, genetic silencing studies have established that the oncogenic activity of tumors lacking SMARCA4 is primarily driven by its paralog SMARCA2 containing residual SWI/SNF complex, suggesting the importance of targeting SMARCA2. Considering this well-established biological rationale, selective inhibition/degradation of either of these proteins should be very useful in precision oncology to achieve immense therapeutic benefit. Here we report selective degraders targeting either SMARCA4 or SMARCA2 that demonstrate distinct cellular phenotype. Methods and Results: 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. A choice of linkers and different exit vectors were considered to construct a variety of heterobifunctional as well as monovalent degrader molecules. Our proprietary ternary complex modeling algorithm, ALMOND (ALgorithm for MOdeling Neosubstrate Degraders) helped in prioritizing the designs. Shortlisted compounds were synthesized and profiled in multiple cellular assays to understand their degradation potential. Several compounds that potently degrade either SMARCA2 or SMARCA4 selectively were identified. These compounds have shown distinct phenotype depending on the lineage as well as SMARCA2 and SMARCA4 status of the cell lines. As expected, SMARCA2 selective degraders showed exquisite sensitivity to SMARCA4 mutant cell lines (SK-MEL-5 & RERF-LC-A1 etc), whereas SMARCA4 selective degraders showed a distinct cellular sensitivity profile. Potent and selective compounds are being optimized further for their pharmacokinetic properties. Conclusions: Highly potent and selective degraders of either SMARCA2 or SMARCA4 were identified. While selective SMARCA2 degraders have been reported in the literature, to the best of our knowledge, no SMARCA4 selective degrader has been reported so far. Distinct cellular selectivity of these paralog selective degraders supports their further optimization towards advancing them to clinical trials. Citation Format: Chandrasekhar Abbineni, Kiran Aithal, Leena Khare, Sandeep Dukare V, Bilash Kuila, Megha Goyal, Khaji Abdul Rawoof, Dhaytadak Bhagwan Mahadeo, Bhagya M S Kumar, Premkumar M, Swetangini Sahu, Suraj T Gore, Lavanya Krishna N, Charamanna KB, Gopinath CH, Samiulla D S, Subhendu Mukherjee, Thomas Antony, Sanjeev Giri, Shekar Chelur, Kavitha Nellore, Girish Daginakatte, Murali Ramachandra, Susanta Samajdar. Identification of paralog selective degraders of SMARCA2 and SMARCA4 for treatment of various cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A046.