Ying Shilong, Chi Hongli, Wu Xiaoqiu, Zeng Pingping, Chen Jinling, Fu Ting, Fu Weitao, Zhang Penghui, Tan Weihong
The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
College of Materials Science and Engineering, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China.
J Med Chem. 2024 Oct 10;67(19):17053-17069. doi: 10.1021/acs.jmedchem.3c02417. Epub 2024 Sep 30.
c-Met is an attractive therapeutic target in multiple tumors. Previous studies have discovered some effective proteolysis-targeting chimeras (PROTACs) able to degrade c-Met; however, the structure-activity relationship (SAR), degradation selectivity, and pharmacokinetic profiles of c-Met PROTACs have, to date, remained largely unknown. Herein, through extensive SAR studies on various warheads, linkers, and E3 ligase ligands, a novel potent c-Met PROTAC was identified. Our results suggested that could induce robust c-Met degradation with excellent selectivity (DC = 6.21 nM), substantially killing the c-Met-addicted cancer cells (IC = 4.37 nM). Furthermore, in vivo studies showed that could achieve excellent oral bioavailability and c-Met degradation, strongly retarding tumor growth with minute organ toxicity. Overall, this study reveals that targeted degradation of c-Met is a promising strategy for the treatment of c-Met-addicted cancers and provides novel lead compounds for the clinical translation of c-Met PROTACs.
c-Met是多种肿瘤中一个有吸引力的治疗靶点。先前的研究已经发现了一些能够降解c-Met的有效蛋白酶靶向嵌合体（PROTAC）；然而，迄今为止，c-Met PROTAC的构效关系（SAR）、降解选择性和药代动力学特征在很大程度上仍不清楚。在此，通过对各种弹头、连接子和E3连接酶配体进行广泛的SAR研究，鉴定出了一种新型强效c-Met PROTAC。我们的结果表明，该化合物能够以优异的选择性（DC = 6.21 nM）诱导强烈的c-Met降解，大量杀死对c-Met成瘾的癌细胞（IC = 4.37 nM）。此外，体内研究表明，该化合物能够实现优异的口服生物利用度和c-Met降解，以微小的器官毒性强烈抑制肿瘤生长。总体而言，本研究表明，靶向降解c-Met是治疗对c-Met成瘾癌症的一种有前景的策略，并为c-Met PROTAC的临床转化提供了新的先导化合物。
