Abstract 1138: Novel SMARCA2 degrading bifunctional molecules as therapeutics in SMARCA4 mutant lung cancer

Abstract Lung cancer is the top cause of cancer mortality. Despite recent advances, the majority of patients with lung cancer still lack effective therapeutic options, underscoring the dire need for additional treatment approaches. Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. Recent reports, and our own data, have identified the paralogue SMARCA2 to be synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. To overcome this hurdle, we have utilized iterative structure-activity relationship (SAR) studies to develop novel, potent and selective SMARCA2 degrading small molecules based on proteolysis targeting chimera (PROTAC) technology. We demonstrated that YD23, our lead SMARCA2 PROTAC, potently and selectively induces degradation of SMARCA2. Using global proteomic analysis and quantification of more than 8000 proteins, we showed that our SMARCA2 PROTAC is highly selective for SMARCA2. Importantly, we showed that YD23 selectively inhibits growth of SMARCA4 mutant lung cancer cells in vitro. Mechanistically, we demonstrated that YD23 reduces chromatin accessibility only in SMARCA4 deficient cells. In particular, YD23 profoundly decreased chromatin accessibility at enhancers of a number of genes including cell cycle and cell growth regulatory genes. Gene expression profiling and pathway analysis indicated that various cell cycle genes were downregulated by YD23 consistent with the reduced chromatin accessibility at their regulatory regions. In conclusion, our study provides a potent chemical probe for studying the synthetic lethal interaction between SMARCA2 and SMARCA4, dissect the chromatin and epigenetic landscape alterations and lay the foundation for future preclinical and clinical development of SMARCA2 degraders as therapeutics. Citation Format: Sasi Kotagiri, Nicholas Blazanin, Yuanxin Xi, Jing Wang, Yonathan Lissanu. Novel SMARCA2 degrading bifunctional molecules as therapeutics in SMARCA4 mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1138.