A development of chimeric VEGFR2 TK inhibitor based on two ligand conformers from PDB: 1Y6A complex--medicinal chemistry consequences of a TKs analysis

Eur J Med Chem. 2014 Jan 24;72:146-59. doi: 10.1016/j.ejmech.2013.11.023. Epub 2013 Dec 1.


VEGFR2 is an important mediator of angiogenesis and influences fate of some cancer stem cells. Here we analysed all 34 structures of VEGFR2 TK available from PDB database. From them a complex PDB: 1Y6A has an exceptional AAZ ligand bound to TK in form of two conformers (U- and S-shaped). This observation inspired us to develop three chimeric bispyridyl VEGFR2 inhibitors by combining structural features of both AAZ conformers and/or their relative ligand AAX (PDB: 1Y6B). Our most interesting inhibitor 22SYM has an enzymatic VEGFR2 TK activity (IC50: 15.1 nM) comparable or better to the active compounds from clinical drugs Nexavar and Sutent. 22SYM inhibits growth, migration and tube formation of endothelial cells (EC) and selectively induces EC apoptosis. 22SYM also inhibits in vivo angiogenesis in Zebrafish embryo assay. Additionally to the above results, we proved here that tyrosine kinases in an inactive form possessing Type I inhibitors can adopt both a closed or an opened conformation of kinase A-loop independently on their DFG-out arrangement. We proposed here that an activity of certain Type I inhibitors (e.g. 22SYM-like) in complex with DFG-out TK can be negatively influenced by collisions with a dynamically moving TK A-loop.

Keywords: Angiogenesis sorafenib Nexavar sunitinib Sutent oxazole; Flexible tyrosine kinase activation loop; HTPMEGBLXVAKBQ-UHFFFAOYSA-N; JQHYGGAREUQSFO-UHFFFAOYSA-N; Medicinal chemistry consequences; NACPZCJMBBHZEB-UHFFFAOYSA-N; Properties of VEGFR-2 tyrosine kinase variants; SELRMMCYEMBVON-UHFFFAOYSA-N; SPZMRCAVVHLMHS-UHFFFAOYSA-N; Type I inhibitor DFG-out A-loop/ligand collision.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Apoptosis / drug effects
  • Chemistry, Pharmaceutical
  • Dose-Response Relationship, Drug
  • Endothelial Cells / drug effects
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Neovascularization, Physiologic / drug effects
  • Oxazoles / chemical synthesis
  • Oxazoles / chemistry
  • Oxazoles / pharmacology*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis
  • Sulfones / chemistry
  • Sulfones / pharmacology*
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Zebrafish


  • Angiogenesis Inhibitors
  • Ligands
  • Oxazoles
  • Protein Kinase Inhibitors
  • Sulfones
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2