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

• DOI: 10.1158/1078-0432.c.6532938.v1
• Publication Date: 2023-04-01T05:58:09Z
• Authors: 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
• Keywords: Bendamustine

<div>AbstractPurpose:<p>Development of B-cell lymphoma 2 (BCL-2)–specific inhibitors poses unique challenges in drug design because BCL-2 homology domain 3 (BH3) shared between family members and the shallow surface their protein–protein interactions. We report herein discovery extensive preclinical investigation lisaftoclax (APG-2575).</p>Experimental Design:<p>Computational modeling was used to “lead” compounds. Biochemical binding, mitochondrial BH3 profiling, cell-based viability or apoptosis assays were determine selectivity potency inhibitor lisaftoclax. The antitumor effects also evaluated several xenograft models.</p>Results:<p>Lisaftoclax selectively binds (Ki < 0.1 nmol/L), disrupts BCL-2:BIM complexes, compromises outer membrane potential, culminating BAX/BAK-dependent, caspase-mediated apoptosis. Lisaftoclax exerted strong activity hematologic cancer cell lines tumor cells from patients with chronic lymphocytic leukemia, multiple myeloma, Waldenström macroglobulinemia. After treatment, prodeath proteins BCL-2‒like protein 11 (BIM) Noxa increased, BIM translocated cytosol mitochondria. Consistent these apoptotic activities, entered malignant rapidly, reached plateau hours, significantly downregulated respiratory function ATP production. Furthermore, inhibited growth models, correlating caspase activation, poly (ADP-ribose) polymerase 1 cleavage, pharmacokinetics compound. combined rituximab bendamustine/rituximab enhanced <i>in vivo</i>.</p>Conclusions:<p>These findings demonstrate that is a novel, orally bioavailable mimetic BCL-2–selective considerable potential for treatment certain malignancies.</p></div>