Discovery of 8-Amino-Substituted 2-Phenyl-2,7-Naphthyridinone Derivatives as New c-Kit/VEGFR-2 Kinase Inhibitors

Molecules. 2019 Dec 5;24(24):4461. doi: 10.3390/molecules24244461.

Abstract

The 2,7-naphthyridone scaffold has been proposed as a novel lead structure of MET inhibitors by our group. To broaden the application of this new scaffold, a series of 8-amino-substituted 2-phenyl-2,7-naphthyridin-1(2H)-one derivatives were designed and synthesized. Preliminary biological screening resulted in the discovery of a new lead of c-Kit and VEGFR-2 kinase inhibitors. Compound 9k exhibited excellent c-Kit inhibitory activity, with an IC50 value of 8.5 nM, i.e., it is 38.8-fold more potent than compound 3 (IC50 of 329.6 nM). Moreover, the compounds 10l and 10r exhibited good VEGFR-2 inhibitory activity, with IC50 values of 56.5 and 31.7 nM, respectively, i.e., they are 5.0-8.8-fold more potent than compound 3 (IC50 of 279.9 nM). Molecular docking experiments provided further insight into the binding interactions of the new lead compounds with c-Kit and VEGFR-2 kinase. In this study, an 8-amino-substituted 2-phenyl-2,7-naphthyridin-1(2H)-one scaffold was identified as the new lead structure of c-Kit and VEGFR-2 kinase inhibitors.

Keywords: 2,7-naphthyridone; VEGFR-2; c-Kit; kinase inhibitor.

MeSH terms

  • Drug Discovery*
  • Humans
  • Molecular Docking Simulation*
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Proto-Oncogene Proteins c-kit* / antagonists & inhibitors
  • Proto-Oncogene Proteins c-kit* / chemistry
  • Vascular Endothelial Growth Factor Receptor-2* / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2* / chemistry

Substances

  • Protein Kinase Inhibitors
  • KDR protein, human
  • KIT protein, human
  • Proto-Oncogene Proteins c-kit
  • Vascular Endothelial Growth Factor Receptor-2