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

Hongchuang Xu; Minshu Wang; Fengxu Wu; Linsheng Zhuo; Wei Huang; Nengfang She

doi:10.1016/j.bmc.2020.115555

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. Epub 2020 May 12.

Authors

Hongchuang Xu¹, Minshu Wang¹, Fengxu Wu¹, Linsheng Zhuo², Wei Huang³, Nengfang She⁴

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: zhuolinsheng199010@126.com.
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: weihuangwuhan@126.com.
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: nfshe@mail.ccnu.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design*
Humans
Mice
Molecular Docking Simulation
Naphthyridines / chemistry*
Naphthyridines / metabolism
Naphthyridines / pharmacology
Naphthyridines / therapeutic use
Neoplasms / drug therapy
Neoplasms / pathology
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / metabolism
Quinolines / chemistry*
Structure-Activity Relationship
Transplantation, Heterologous
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Naphthyridines
Protein Kinase Inhibitors
Quinolines
Proto-Oncogene Proteins c-met
Vascular Endothelial Growth Factor Receptor-2