2. Academic Validation
  3. A novel Apigenin derivative suppresses renal cell carcinoma via directly inhibiting wild-type and mutant MET

A novel Apigenin derivative suppresses renal cell carcinoma via directly inhibiting wild-type and mutant MET

  • Biochem Pharmacol. 2021 Aug;190:114620. doi: 10.1016/j.bcp.2021.114620.
Jing Li 1,  Guishan Tan 2,  Yabo Cai 3,  Ruihuan Liu 4,  Xiaolin Xiong 3,  Baohua Gu 3,  Wei He 3,  Bing Liu 3,  Qingyun Ren 3,  Jianping Wu 1,  Bo Chi 3,  Hang Zhang 3,  Yanzhong Zhao 5,  Yangrui Xu 1,  Zhenxing Zou 1,  Fenghua Kang 1,  Kangping Xu 6
Affiliations

Affiliations

  • 1 Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China.
  • 2 Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China; Xiangya Hospital of Central South University, Changsha 410008, China.
  • 3 State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Co. Ltd, Dongguan 523871, China.
  • 4 Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China; Zhuzhou Qianjin Pharmaceutical Co. Ltd, Zhuzhou, 412007, China.
  • 5 The Third Xiangya Hospital, Central South University, Changsha 410013, China.
  • 6 Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China. Electronic address: xukp395@csu.edu.cn.
PMID: 34043966 DOI: 10.1016/j.bcp.2021.114620
Abstract

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.

Keywords

Apigenin derivatives; Drug-resistant MET mutations; MET; MET downstream signaling; Renal cell carcinoma.

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