Ascentage Pharma (Suzhou) Co., Ltd., Suzhou, Jiangsu, China.
Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida.
Clin Cancer Res. 2022 Dec 15;28(24):5455-5468. doi: 10.1158/1078-0432.CCR-21-4037.
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.
由于 BCL-2 家族成员的 B 细胞淋巴瘤 2（BCL-2）同源结构域 3（BH3）同源性和其蛋白-蛋白相互作用的浅表面，BCL-2 特异性抑制剂的开发在药物设计中带来了独特的挑战。本文报告了 BCL-2 选择性抑制剂 lisaftoclax（APG-2575）的发现和广泛的临床前研究。
计算建模用于设计“先导”化合物。生化结合、线粒体 BH3 分析以及基于细胞的活力或凋亡测定用于确定 BCL-2 抑制剂 lisaftoclax 的选择性和效力。lisaftoclax 的抗肿瘤作用也在几种异种移植模型中进行了评估。
lisaftoclax 选择性结合 BCL-2（Ki<0.1 nmol/L），破坏 BCL-2:BIM 复合物，并破坏线粒体外膜电位，最终导致 BAX/BAK 依赖性、半胱天冬酶介导的凋亡。lisaftoclax 在血液系统恶性肿瘤细胞系和慢性淋巴细胞白血病、多发性骨髓瘤或瓦尔登斯特伦巨球蛋白血症患者的肿瘤细胞中表现出强大的抗肿瘤活性。在 lisaftoclax 治疗后，促死亡蛋白 BCL-2 样蛋白 11（BIM）和 Noxa 增加，BIM 从细胞质易位到线粒体。与这些凋亡活性一致，lisaftoclax 迅速进入恶性细胞，在 2 小时内达到平台期，并显著下调线粒体呼吸功能和 ATP 产生。此外，lisaftoclax 抑制异种移植模型中的肿瘤生长，与半胱天冬酶激活、多聚（ADP-核糖）聚合酶 1 切割和化合物的药代动力学相关。lisaftoclax 与利妥昔单抗或苯达莫司汀/利妥昔单抗联合使用可增强体内抗肿瘤活性。
这些发现表明，lisaftoclax 是一种新型、口服生物可利用的 BH3 模拟物 BCL-2 选择性抑制剂，具有治疗某些血液恶性肿瘤的巨大潜力。
