Abstract 3879: Development of potent, highly selective and efficacious SMARCA2 degraders

Abstract In human lung, melanoma and other types of human cancers, the mammalian SWItch/Sucrose Non-Fermentable (SWI/SNF) helicase SMARCA4 is frequently mutated, which leads to inactivation of its functions. SMARCA2, a close homologous protein of SMARCA4, is an attractive synthetic lethality target for human cancers with SMARCA4 deficiency. Herein, we report the discovery and biological evaluation of potent, highly selective and efficacious SMARCA2 PROTAC degraders exemplified by UM-SMD-3236. UM-SMD-3236 has a DC50 value of 1 nM in inducing degradation of SMARCA2 in cells and demonstrates 400-fold selectivity over SMARCA4 protein. Of significance, while UM-SMD-3236 achieves a Dmax of 95% against SMARCA2, it shows a Dmax of 50% against SMARCA4 in cells. In vivo, a single intravenous dose of UM-SMD-3236 attains 85-93% of SMARCA2 depletion in tumor tissues for 7 days, while showing no reduction of the SMARCA4 protein. Weekly intravenous administration of UM-SMD-3236 is highly effective in inhibition of tumor growth in SMARCA4 deficient xenograft models of human cancer. Importantly, UM-SMD-3236 shows no signs of toxicity in mice at highly efficacious doses. UM-SMD-3236 represents a highly promising SMARCA2 degrader for extensive evaluation as a potential new therapy for the treatment of SMARCA4-deficient human cancers. References 1. Oike, T. ; Ogiwara, H. ; Tominaga, Y. ; Ito, K. ; Ando, O. ; Tsuta, K. ; Mizukami, T. ; Shimada, Y. ; Isomura, H. ; Komachi, M. ; Furuta, K. ; Watanabe, S. -I. ; Nakano, T. ; Yokota, J. ; Kohno, T. A Synthetic Lethality-Based Strategy to Treat Cancers Harboring a Genetic Deficiency in the Chromatin Remodeling Factor BRG1. Cancer Res. 2013, 73, 5508-5518. 2. Yang, L. ; Tu, W. ; Huang, L. ; Miao, B. ; Kaneshige, A. ; Jiang, W. ; Leng, L. ; Wang, M. ; Wen, B. ; Sun, D. ; Wang, S. Discovery of SMD-3040 as a Potent and Selective SMARCA2 PROTAC Degrader with Strong in vivo Antitumor Activity. J. Med. Chem. 2023, 66, 10761-10781. Citation Format: Lin Yang, Wenbin Tu, Liyue Huang, Lingying Leng, Wei Jiang, Meilin Wang, Bo Wen, Duxin Sun, Jeanne Stuckey, Shaomeng Wang. Development of potent, highly selective and efficacious SMARCA2 degraders abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3879.