Structure-based drug design of 1,3,5-triazine and pyrimidine derivatives as novel FGFR3 inhibitors with high selectivity over VEGFR2

Bioorg Med Chem. 2020 May 15;28(10):115453. doi: 10.1016/j.bmc.2020.115453. Epub 2020 Mar 28.

Abstract

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer. We identified 1,3,5-triazine derivative 18b and pyrimidine derivative 40a as novel structures with potent and highly selective FGFR3 inhibitory activity over vascular endothelial growth factor receptor 2 (VEGFR2) using a structure-based drug design (SBDD) approach. X-ray crystal structure analysis suggests that interactions between 18b and amino acid residues located in the solvent region (Lys476 and Met488), and between 40a and Met529 located in the back pocket of FGFR3 may underlie the potent FGFR3 inhibitory activity and high kinase selectivity over VEGFR2.

Keywords: Fibroblast growth factor receptor 3; Kinase selectivity; Structure activity relationships; Structure-based drug design; Vascular endothelial growth factor receptor 2; X-ray crystal structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Molecular Structure
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptor, Fibroblast Growth Factor, Type 3 / antagonists & inhibitors*
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism
  • Structure-Activity Relationship
  • Triazines / chemistry
  • Triazines / pharmacology*
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Protein Kinase Inhibitors
  • Pyrimidines
  • Triazines
  • FGFR3 protein, human
  • KDR protein, human
  • Receptor, Fibroblast Growth Factor, Type 3
  • Vascular Endothelial Growth Factor Receptor-2
  • pyrimidine