Jing Deng, Aneel Paulus, Douglas D Fang, Alak Manna, Guangfeng Wang, Hengbang Wang, Saijie Zhu, Jianyong Chen, Ping Min, Yan Yin, Navnita Dutta, Nabanita Halder, Gina Ciccio, John A Copland, James Miller, Bing Han, Longchuan Bai, Liu Liu, Mi Wang, Donna McEachern, Sally Przybranowski, Chao-Yie Yang, Jeanne A Stuckey, Depei Wu, Caixia Li, Jeremy Ryan, Anthony Letai, Sikander Ailawadhi, Dajun Yang, Shaomeng Wang, Asher Chanan-Khan, Yifan Zhai
PURPOSE: Development of BCL-2-specific inhibitors poses unique challenges in drug design because of BCL-2 homology domain 3 (BH3) shared homology between BCL-2 family members and the shallow surface of their protein-protein interactions. We report herein discovery and extensive preclinical investigation of lisaftoclax (APG-2575). EXPERIMENTAL DESIGN: Computational modeling was used to design "lead" compounds. Biochemical binding, mitochondrial BH3 profiling, and cell-based viability or apoptosis assays were used to determine the selectivity and potency of BCL-2 inhibitor lisaftoclax...
September 1, 2022: Clinical Cancer Research