Rational Design, Synthesis, and Biological Evaluation of Novel c-Met Degraders for Lung Cancer Therapy

  • J Med Chem. 2025 Feb 13;68(3):2815-2839. doi: 10.1021/acs.jmedchem.4c02129.
Xingyang Qiu  1 ,  Qingquan Zheng  1 ,  Dongdong Luo  1 ,  Yue Ming  1 ,  Tingting Zhang  1 ,  Wenchen Pu  1 ,  Min Ai  1 ,  Jianhua He  1 ,  Yong Peng  1  2
Affiliations
  • 1. Center for Molecular Oncology, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, 610064 Chengdu, China.
  • 2. Frontiers Medical Center, Tianfu Jincheng Laboratory, 610212 Chengdu, China.
PMID: 39882685 DOI: 10.1021/acs.jmedchem.4c02129
Abstract

Cellular-mesenchymal epithelial transition factor (c-Met) is an attractive target for treating multiple cancers. Despite plentiful c-Met inhibitors have been developed, some issues, including the acquired drug resistance to c-Met inhibitors, have emerged to hamper their application in clinical treatment. Degradation of c-Met offers an opportunity to solve these issues. In this study, we developed a series of c-Met degraders, and the optimal compound 22b can efficiently degrade c-Met with a DC50 value of 0.59 nM in EBC-1 cells. Mechanistic studies revealed that compound 22b induced c-Met degradation via proteasome-mediated pathway. In addition, compound 22b suppressed the proliferation and also induced Apoptosis of EBC-1 cells, outperforming the corresponding inhibitor tepotinib. Importantly, compound 22b showed favorable pharmacokinetic properties and significantly induced tumor regression in a xenograft model without obvious toxicity. In brief, this study provided compound 22b as a novel c-Met degrader for lung Cancer therapy.

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