A novel Apigenin derivative suppresses renal cell carcinoma via directly inhibiting wild-type and mutant MET.
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 auto-phosphorylation 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.
['Li|Jing|J|', 'Tan|Guishan|G|', 'Cai|Yabo|Y|', 'Liu|Ruihuan|R|', 'Xiong|Xiaolin|X|', 'Gu|Baohua|B|', 'He|Wei|W|', 'Liu|Bing|B|', 'Ren|Qingyun|Q|', 'Wu|Jianping|J|', 'Chi|Bo|B|', 'Zhang|Hang|H|', 'Zhao|Yanzhong|Y|', 'Xu|Yangrui|Y|', 'Zou|Zhenxing|Z|', 'Kang|Fenghua|F|', 'Xu|Kangping|K|']
D000818:Animals D000970:Antineoplastic Agents D047310:Apigenin D002277:Carcinoma D020134:Catalytic Domain D002453:Cell Cycle D045744:Cell Line, Tumor D049109:Cell Proliferation D015972:Gene Expression Regulation, Neoplastic D006801:Humans D007680:Kidney Neoplasms D051379:Mice D008819:Mice, Nude D062105:Molecular Docking Simulation D015394:Molecular Structure D009154:Mutation D009374:Neoplasms, Experimental D008517:Phytotherapy D011487:Protein Conformation D019859:Proto-Oncogene Proteins c-met
Apigenin derivatives Renal cell carcinoma MET Drug-resistant MET mutations MET downstream signaling