Selective and Orally Bioavailable c-Met PROTACs for the Treatment of c-Met-Addicted Cancer

  • J Med Chem. 2024 Oct 10;67(19):17053-17069. doi: 10.1021/acs.jmedchem.3c02417.
Shilong Ying  1 ,  Hongli Chi  1 ,  Xiaoqiu Wu  1 ,  Pingping Zeng  2 ,  Jinling Chen  1 ,  Ting Fu  1 ,  Weitao Fu  3 ,  Penghui Zhang  1 ,  Weihong Tan  1  4
Affiliations
  • 1. 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.
  • 2. College of Materials Science and Engineering, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China.
  • 3. Insitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China.
  • 4. Institute of Molecular Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
PMID: 39348183 DOI: 10.1021/acs.jmedchem.3c02417
Abstract

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 Met-DD4 was identified. Our results suggested that Met-DD4 could induce robust c-Met degradation with excellent selectivity (DC50 = 6.21 nM), substantially killing the c-Met-addicted Cancer cells (IC50 = 4.37 nM). Furthermore, in vivo studies showed that Met-DD4 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.

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