2. Academic Validation
  3. Crizotinib-based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation

Crizotinib-based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation

  • Cancer Sci. 2023 May;114(5):1958-1971. doi: 10.1111/cas.15733.
Jin-Jiao Chen 1 2,  Jin-Mei Jin 1,  Wen-Jie Gu 1,  Zeng Zhao 3 4,  Hu Yuan 1,  Yu-Dong Zhou 1 5,  Dale G Nagle 1 6,  Qiu-Lei Xi 7,  Xue-Mei Zhang 2,  Qing-Yan Sun 4,  Ye Wu 1,  Wei-Dong Zhang 1,  Xin Luan 1
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 2 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
  • 3 School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
  • 4 State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, China.
  • 5 Department of Chemistry and Biochemistry, College of Liberal Arts, University of Mississippi, Boston, Massachusetts, USA.
  • 6 Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Boston, Massachusetts, USA.
  • 7 Department of General Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China.
PMID: 36692137 DOI: 10.1111/cas.15733
Abstract

As one of the common malignant Cancer types, gastric Cancer (GC) is known for late-stage diagnosis and poor prognosis. Overexpression of the receptor tyrosine kinase MET is associated with poor prognosis among patients with advanced stage GC. However, no Met Inhibitor has been used for GC treatment. Like other tyrosine kinase inhibitors that fit the "occupancy-driven" model, current MET inhibitors are prone to acquired resistance. The emerging proteolysis targeting chimera (PROTAC) strategy could overcome such limitations through direct degradation of the target proteins. In this study, we successfully transformed the MET-targeted inhibitor crizotinib into a series of PROTACs, recruiting Cereblon/cullin 4A E3 ubiquitin ligase to degrade the MET proteins. The optimized lead PROTAC (PRO-6 E) effectively eliminated MET proteins in vitro and in vivo, inhibiting proliferation and motility of MET-positive GC cells. In the MKN-45 xenograft model, PRO-6 E showed pronounced antitumor efficacy with a well-tolerated dosage regimen. These results validated PRO-6 E as the first oral PROTAC for MET-dependent GC.

Keywords

MET; gastric cancer; proteolysis targeting chimera; receptor tyrosine kinase; ubiquitin-mediated proteasome degradation.

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