Abstract 6289: Enhancer reprogramming by novel SMARCA2 degrading PROTACs underlies therapeutic utility in SMARCA4 mutant tumors

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, as well as 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. Mechanistically, we demonstrated that YD23 reduces chromatin accessibility only in SMARCA4-deficient cells with profoundly decreased chromatin accessibility at enhancer regions. Gene expression profiling and pathway analysis indicated that core cell cycle genes were downregulated by YD23 and is consistent with reduced chromatin accessibility at their regulatory regions. Furthermore, integrative analysis of RNA-seq and ATAC-seq revealed a strong correlation between gene expression and enhancer accessibility changes by YD23. In particular, we identified the mitotic regulator NEDD9 as a critical target in enhancers that are strongly reduced by YD23 in SMARCA4-deficient lung cancer cells. In conclusion, our study provides a promising 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. Enhancer reprogramming by novel SMARCA2 degrading PROTACs underlies therapeutic utility in SMARCA4 mutant tumors [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 6289.