Abstract 405: Discovery of GLR203101, a selective and orally bioavailable PROTAC of SMARCA2 for the treatment of SMARCA4 mutant tumors

Abstract The SWI/SNF (mammalian SWItch/Sucrose Non-Fermentable) helicase SMARCA4 is frequently mutated in cancer. Its inactivation results in a cellular dependence on its paralog, SMARCA2, for survival. Therefore, SMARCA2 constitutes an attractive therapeutic synthetic lethality target. However, the co-deletion of Smarca2 and Smarca4 in adult mice was lethal, highlighting the necessity for designing molecules that target SMARCA2 selectively. This objective is rather challenging due to the high homology of SMARCA2/4. Few SMARCA2 selective compounds have entered clinical trials, including PROTAC molecule PRT-3789 administered by intravenous injection in phase 2 clinical trials. Herein, we report the discovery of a selective and orally bioavailable SMARCA2 PROTAC degrader, GLR203101. Notably, our lead compound GLR203101 possesses a favorable molecular weight (< 650), contributing to excellent physical and chemical properties. GLR203101 exhibited robust degradation of SMARCA2 (DC50 < 10 nM, Dmax > 80%) over SMARCA4 (Dmax < 10%) in Hela cell line using HiBiT assay. The degradation selectivity was also validated by western blot in several SMARCA4 wild-type cell lines, including Hela, MV-4-11, LNCaP and SW1573. GLR203101 also selectively inhibited the viability of SMARCA4-deficient cancer cells with low nanomolar IC50 values, showing >1000-fold selectivity over SMARCA4 wild-type cell lines. In addition, GLR203101 exhibited favorable PK properties with high exposure and moderate oral bioavailability in mice and SD rats. After 24 hours of oral administration of GLR203101, a robust degradation of SMARCA2 while sparing SMARCA4 was observed in transplanted tumors in the xenograft model. GLR203101 is being evaluated as a preclinical candidate. Citation Format: Xiaoguang Li, Siyu Gu, Yongzheng Ding, Jing Cheng, Kanghua Wang, Weiwei Yu, Wenmin Chen, Fuming Xu. Discovery of GLR203101, a selective and orally bioavailable PROTAC of SMARCA2 for the treatment of SMARCA4 mutant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 405.