Journal
BIOCHEMICAL PHARMACOLOGY
Volume 190, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2021.114620
Keywords
Apigenin derivatives; Renal cell carcinoma; MET; MET downstream signaling; Drug-resistant MET mutations
Categories
Funding
- Construction Program of Hunan's innovative Province (CN) -High-tech Industry Science and Technology Innovation Leading Project [2020SK2002]
- Central South University postgraduate independent exploration and innovation project [2018zzts239, 2020zzts821]
- Key Project of Changsha Science and Technology Plan [kq1801072]
- National Natural Science Foundation of China [31370370]
- Central South University Deepening Innovation and Entrepreneurship Education Reform Research Project [2019CG006]
- Hunan Province Ordinary Higher Education Teaching Reform Research Project
- Open Sharing Fund for the Large-scale Instruments and Equipments of Central South University
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Compound 15e shows potential as a treatment for renal cell carcinoma by inhibiting MET activation and overcoming drug resistance.
MET, the receptor of hepatocyte growth factor (HGF), is a driving factor in renal cell carcinoma (RCC) and also a proven drug target for cancer treatment. To improve the activity and to investigate the mechanisms of action of Apigenin (APG), novel derivatives of APG with improved properties were synthesized and their activities against Caki-1 human renal cancer cell line were evaluated. It was found that compound 15e exhibited excellent potency against the growth of multiple RCC cell lines including Caki-1, Caki-2 and ACHN and is superior to APG and Crizotinib. Subsequent investigations demonstrated that compound 15e can inhibit Caki-1 cell proliferation, migration and invasion. Mechanistically, 15e directly targeted the MET kinase domain, decreased its autophosphorylation at Y1234/Y1235 and inhibited its kinase activity and downstream signaling. Importantly, 15e had inhibitory activity against mutant MET V1238I and Y1248H which were resistant to approved MET inhibitors Cabozantinib, Crizotinib or Capmatinib. In vivo tumor graft study confirmed that 15e repressed RCC growth through inhibition of MET activation. These results indicate that compound 15e has the potential to be developed as a treatment for RCC, and especially against drug-resistant MET mutations.
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