2. Academic Validation
  3. Novel Highly Potent c-Met Degraders against a Broad Range of Cancers

Novel Highly Potent c-Met Degraders against a Broad Range of Cancers

  • J Med Chem. 2025 Jul 24;68(14):15176-15197. doi: 10.1021/acs.jmedchem.5c01470.
Changkai Jia 1 2,  Pengli Wei 1 3,  Shiyang Sun 1 2,  Yaqiu Mao 1 3,  Ting Wei 1 2,  Zhenze Qi 1 2,  Fan Feng 4,  Yalei Wang 1 2,  Xu Cai 1 2,  Zhiyuan Zhao 1 2,  Bingkun Li 1 2,  Min Qiao 1 2,  Yaxin Zou 1 2,  Ziyun Zhang 1 2,  Tingting Yang 5,  Xiaomei Zhuang 2,  Junhai Xiao 1 2,  Xuesong Feng 3,  Pengyun Li 1 2,  Zhibing Zheng 1 2,  Song Li 1 2
Affiliations

Affiliations

  • 1 National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
  • 2 State Key Laboratory of National Security Specially Needed Medicines, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
  • 3 School of Pharmacy, China Medical University, Shenyang 110122, China.
  • 4 Department of Clinical Laboratory, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China.
  • 5 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
PMID: 40665847 DOI: 10.1021/acs.jmedchem.5c01470
Abstract

The cellular-mesenchymal epithelial transition factor (c-Met) is an attractive target in multiple cancers. Despite various c-Met inhibitors having been developed, the acquired drug resistance hampers their clinical application. In this study, through elaborately rational optimization, c-Met degraders, namely, D19, D26, and G4, were developed to exhibit single-digit nanomolar cell growth inhibition IC50 values, picomolar c-Met degradation DC50 values, and >99% of maximum degradation in Cancer cells with MET alterations via a Cullin-CRBN-dependent pathway. Moreover, D19 and G4 showed favorable pharmacokinetic properties and their oral administration induced complete EBC-1 xenograft tumor inhibition. Notably, D19 and G4 achieved nanomolar inhibitory activity and degradation efficacy against tepotinib-resistant Cancer cells harboring c-MetD1228N and c-MetY1230H mutations. Furthermore, the synergetic effects of D19 with epidermal growth factor receptor/HER2, vascular endothelial growth factor receptor, and BRAF inhibitors were shown in inhibiting various types of tumor cells. Overall, this study demonstrates that D19 and G4 serve as promising candidates for the treatment of MET-driven cancers.

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