2. Academic Validation
  3. Discovery of 1,6-naphthyridinone-based MET kinase inhibitor bearing quinoline moiety as promising antitumor drug candidate

Discovery of 1,6-naphthyridinone-based MET kinase inhibitor bearing quinoline moiety as promising antitumor drug candidate

  • Eur J Med Chem. 2020 Apr 15;192:112174. doi: 10.1016/j.ejmech.2020.112174.
Tao Chen 1,  Lin-Sheng Zhuo 2,  Peng-Fei Liu 2,  Wei-Rong Fang 1,  Yun-Man Li 3,  Wei Huang 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, PR China.
  • 2 Nanjing Natinefy Pharmatech. Co., Ltd., Nanjing, PR China.
  • 3 State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, PR China. Electronic address: yunmanlicpu@163.com.
  • 4 Nanjing Natinefy Pharmatech. Co., Ltd., Nanjing, PR China. Electronic address: weihuangwuhan@126.com.
PMID: 32113049 DOI: 10.1016/j.ejmech.2020.112174
Abstract

A series of 1,6-naphthyridinone-based MET kinase inhibitors bearing quinoline moiety in block A were designed and synthesized based on the structures of Cabozantinib and our reported compound IV. Extensive SAR and DMPK studies led to the identification of 20j, a potent and orally bioavailable MET kinase inhibitor with favorable kinase selectivity. More importantly, 20j exhibited statistically significant tumor growth inhibition (Tumor growth inhibition/TGI of 131%, 4/6 partial regression/PR) in the U-87 MG xeograft model, which is superior to that of Cabozantinib (TGI of 97%, 2/6 PR), and significantly better than that of compound IV (TGI of 15%, 0/6 PR) at the same dose (12.5 mg/kg). Combined with favorable in vitro potency, kinase selectivity, pharmacokinetic profile and in vivo efficacy, the promising antitumor drug candidate 20j has subsequently advanced into preclinical research.

Keywords

1,6-Naphthyridone; Antitumor efficacy; MET kinase inhibitor; Quinoline.

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