2. Academic Validation
  3. Discovery of N-substituted-3-phenyl-1,6-naphthyridinone derivatives bearing quinoline moiety as selective type II c-Met kinase inhibitors against VEGFR-2

Discovery of N-substituted-3-phenyl-1,6-naphthyridinone derivatives bearing quinoline moiety as selective type II c-Met kinase inhibitors against VEGFR-2

  • Bioorg Med Chem. 2020 Jun 15;28(12):115555. doi: 10.1016/j.bmc.2020.115555.
Hongchuang Xu 1,  Minshu Wang 1,  Fengxu Wu 1,  Linsheng Zhuo 2,  Wei Huang 3,  Nengfang She 4
Affiliations

Affiliations

  • 1 Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, China.
  • 2 Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, China. Electronic address: [email protected].
  • 3 Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, China. Electronic address: [email protected].
  • 4 Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, China. Electronic address: [email protected].
PMID: 32503697 DOI: 10.1016/j.bmc.2020.115555
Abstract

New N-substituted-3-phenyl-1,6-naphthyridinone derivatives are designed and synthesized, based on structural modification of our previously reported compound 3. Extensive enzyme-based SAR studies and PK evaluation led to the discovery of compound 4r, with comparable c-Met potency to that of Cabozantinib and high VEGFR-2 selectivity, while Cabozantinib displayed no VEGFR-2 selectivity. More importantly, at oral doses of 45 mg/kg (Q.D.), compound 4r exhibits significant tumor growth inhibition (93%) in a U-87MG human gliobastoma xenograft model. The promising selectivity against VEGFR-2 and excellent tumor growth inhibition of compound 4r suggest that it could be used as a new lead molecule for further discovery of selective type II c-Met inhibitors.

Keywords

1,6-Naphthyridone; Antitumor efficacy; VEGFR-2 selectivity; c-Met kinase inhibitor.

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