Discovery of High-Affinity SMARCA2/4 Bromodomain Ligands and Development of Potent and Exceptionally Selective SMARCA2 PROTAC Degraders
Lingying Leng, Wenbin Tu, Lin Yang, Liyue Huang, Mi Wang, Jennifer L. Meagher, Krishnapriya Chinnaswamy, Srinivasa Rao Allu, Rohan Kalyan Rej, Jelena Tošović, Lalgudi S. Harikrishnan, Zhenwu Li, Zhihua Sui, Jeanne A. Stuckey, Shaomeng Wang
Abstract
In the SWI/SNF chromatin-remodeling complex, the mutually exclusive catalytic ATPase subunits SMARCA2 and SMARCA4 proteins have a synthetic-lethal relationship. Selectively targeting SMARCA2 for degradation is a promising and new therapeutic strategy for human cancers harboring inactivated mutated SMARCA4. In this study, we report the design, synthesis, and biological evaluation of novel SMARCA2/4 ligands and our subsequent design of PROTAC degraders using high-affinity SMARCA ligands and VHL-1 ligands. Our efforts led to the discovery of high-affinity SMARCA2/4 bromodomain ligands and the development of a potent and selective SMARCA2 degrader and a highly potent SMARCA2/4 and PBRM1 degrader.