American Association for Cancer Research
ccr-21-4037_supplementary_materials_and_methods_s1_suppsm1.docx (59.72 kB)

Supplementary Data from Lisaftoclax (APG-2575) Is a Novel BCL-2 Inhibitor with Robust Antitumor Activity in Preclinical Models of Hematologic Malignancy

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journal contribution
posted on 2023-04-01, 00:07 authored by 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
Supplementary Data from Lisaftoclax (APG-2575) Is a Novel BCL-2 Inhibitor with Robust Antitumor Activity in Preclinical Models of Hematologic Malignancy


Ascentage Pharma (亚盛医药是)



Development of B-cell lymphoma 2 (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). 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. The antitumor effects of lisaftoclax were also evaluated in several xenograft models. Lisaftoclax selectively binds BCL-2 (Ki < 0.1 nmol/L), disrupts BCL-2:BIM complexes, and compromises mitochondrial outer membrane potential, culminating in BAX/BAK-dependent, caspase-mediated apoptosis. Lisaftoclax exerted strong antitumor activity in hematologic cancer cell lines and tumor cells from patients with chronic lymphocytic leukemia, multiple myeloma, or Waldenström macroglobulinemia. After lisaftoclax treatment, prodeath proteins BCL-2‒like protein 11 (BIM) and Noxa increased, and BIM translocated from cytosol to mitochondria. Consistent with these apoptotic activities, lisaftoclax entered malignant cells rapidly, reached plateau in 2 hours, and significantly downregulated mitochondrial respiratory function and ATP production. Furthermore, lisaftoclax inhibited tumor growth in xenograft models, correlating with caspase activation, poly (ADP-ribose) polymerase 1 cleavage, and pharmacokinetics of the compound. Lisaftoclax combined with rituximab or bendamustine/rituximab enhanced antitumor activity in vivo. These findings demonstrate that lisaftoclax is a novel, orally bioavailable BH3 mimetic BCL-2–selective inhibitor with considerable potential for the treatment of certain hematologic malignancies.

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