Abstract 6051: Discovery of oral SMARCA2 degraders for the treatment of SMARCA4 mutant tumors

Abstract

Abstract The paralog enzymes SMARCA2 and SMARCA4 are mutually exclusive members within the SWI/SNF chromatin remodeling complex. This complex plays a crucial role in governing gene expression by altering the chromatin and rendering it accessible to transcription machinery. The process of chromatin remodeling by the SWI/SNF complex is dependent on ATP hydrolysis. Within the complex, either SMARCA2 or SMARCA4 serves as the sole component capable of catalyzing ATP hydrolysis and are thereby essential to the activity of the complex. SMARCA4 has been found to be mutated in various cancer types, including non-small cell lung carcinoma, colon adenocarcinoma, bladder, and endometrial cancer. In cancer cells where SMARCA4 is deleted, the functionality of the SWI/SNF complex and cell survival is dependent on the presence of SMARCA2, thereby resulting in synthetic lethality if SMARCA2 is depleted. Utilizing in vitro and in vivo model systems we have discovered potent, selective, and orally bioavailable heterobifunctional degraders targeting SMARCA2. Our lead molecules exhibit potent and selective degradation of SMARCA2 (DC50 < 10 nM) with no impact on SMARCA4 (DC50 > 1000 nM). Furthermore, a striking selective activity in proliferation assays was observed with SMARCA4 deleted cells exhibiting gIC50 ranging from 1 -10 nM and SMARCA4 WT cells > 1000 nM. Oral administration in mice harboring human cancer cell line xenografts revealed dose-dependent and selective in vivo degradation of SMARCA2. Degradation of SMARCA2 led to significant anti-tumor activity in SMARCA4 mutant NSCLC xenograft models. Together, these data demonstrate a foundation for the development of a best-in-class degrader for the treatment of SMARCA4 deleted cancers. Citation Format: Jose C. Clemente, Lal Harikrishnan, Steve Knight, Debangshu Samanta, Zhenwu Li, Rakesh Nagilla, Nathan Kendsersky, Shreyas Joshi, Peter Orth, Matt Tudor, Qiaolin Deng, Clemente Aguilar-Bonavides, Elham Behshad, Zhihua Sui, Corey Strickland, Larry J. Jolivette, Helai P. Mohammad. Discovery of oral SMARCA2 degraders for the treatment of SMARCA4 mutant tumors [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(6_Suppl):Abstract nr 6051.