Hu Xiaoping, Graciano Kevin, Hu Jianping, Liu Chang, Zhang Jiuyi, Xie Ling, Chen Xian, Xiong Yan, Jin Jian, Xu Jia
Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Science, Oncological Science and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, 35294, United States; O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, 35233, United States.
Eur J Med Chem. 2025 Nov 15;298:118006. doi: 10.1016/j.ejmech.2025.118006. Epub 2025 Jul 24.
Aurora kinases, consisting of Aurora A, B, and C, play critical roles in the regulation of mitosis and are frequently overexpressed in multiple types of cancer. Several Aurora kinase inhibitors have been developed and tested in clinical trials. Additionally, Aurora kinase A (AURKA) degraders and dual degraders of AURKA and Aurora kinase B (AURKB) have been reported. However, no AURKB selective degrader has been reported. Here, we report the discovery of the first-in-class AURKB selective degrader, MS44 (18), a von Hippel-Lindau (VHL) E3 ligase-recruiting proteolysis-targeting chimera (PROTAC), which potently degrades AURKB with a DC < 100 nM in a time-, concentration-, VHL-, and ubiquitin-proteasome system (UPS)-dependent manner. Compound 18 selectively degrades AURKB over AURKA and other related kinases. Notably, compound 18 effectively inhibits the proliferation in multiple cancer cell lines. Overall, compound 18 is a valuable chemical biology tool and a potential therapeutic. Our findings suggest that pharmacological degradation of AURKB could offer an alternative therapeutic approach for treating AURKB-dependent tumors.
极光激酶由极光激酶A、B和C组成，在有丝分裂调控中起关键作用，且在多种癌症中经常过度表达。几种极光激酶抑制剂已被开发并在临床试验中进行测试。此外，还报道了极光激酶A（AURKA）降解剂以及AURKA和极光激酶B（AURKB）的双重降解剂。然而，尚未有AURKB选择性降解剂的报道。在此，我们报告了首个AURKB选择性降解剂MS44（18）的发现，它是一种招募冯·希佩尔-林道（VHL）E3连接酶的靶向蛋白水解嵌合体（PROTAC），能以时间、浓度、VHL和泛素-蛋白酶体系统（UPS）依赖的方式，在DC<100 nM时有效降解AURKB。化合物18相对于AURKA和其他相关激酶，能选择性地降解AURKB。值得注意的是，化合物18能有效抑制多种癌细胞系的增殖。总体而言，化合物18是一种有价值的化学生物学工具和潜在的治疗药物。我们的研究结果表明，AURKB的药理学降解可能为治疗依赖AURKB的肿瘤提供一种替代治疗方法。
