Discovery of novel dual VEGFR2 and Src inhibitors using a multistep virtual screening approach

Future Med Chem. 2017 Jan;9(1):7-24. doi: 10.4155/fmc-2016-0162. Epub 2016 Dec 20.


Aim: Simultaneous inhibition of VEGFR2 and Src may enhance the efficacy of VEGFR2-targeted cancer therapeutics. Hence, development of dual inhibitors on VEGFR2 and Src can be a useful strategy for such treatments.

Materials & methods: A multistep virtual screening protocol, comprising ligand-based support vector machines method, drug-likeness rules filter and structure-based molecular docking, was developed and employed to identify dual inhibitors of VEGFR2 and Src from a large commercial chemical library. Kinase inhibitory assays and cell viability assays were then used for experimental validation.

Results: A set of compounds belonging to six different molecular scaffolds was identified and sent for biological evaluation. Compound 3c belonging to the 2-amino-3-cyanopyridine scaffold exhibited good antiproliferative effect and dual-target activities against VEGFR2 and Src.

Conclusion: This study demonstrated the ability of the multistep virtual screening approach to identify novel multitarget agents.

Keywords: 2-amino-3-cyanopyridines; Src; Surflex–Dock; VEGFR2; cancer; combinatorial support vector machines; drug discovery; molecular docking; multikinase inhibitors; virtual screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Drug Evaluation, Preclinical / methods*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • src-Family Kinases / antagonists & inhibitors*
  • src-Family Kinases / metabolism


  • Protein Kinase Inhibitors
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2
  • src-Family Kinases