Small molecule inhibitors of KDR (VEGFR-2) kinase: an overview of structure activity relationships

Curr Top Med Chem. 2002 Sep;2(9):973-1000. doi: 10.2174/1568026023393273.


The Kinase insert Domain containing Receptor (KDR), alternatively referred to as VEGFR-2, is a receptor for Vascular Endothelial Growth Factors (VEGFs) and functions as a key regulator of angiogenesis, the process by which new capillaries are created from preexisting blood vessels. The induction of angiogenesis, or the "angiogenic switch," is a critical step in tumor progression, and inhibitors of KDR have been demonstrated both to induce tumor regression and reduce metastatic potential in preclinical models. In the last few years, medicinal chemists have expanded the kinase selectivity profile of known inhibitor classes to include KDR, and also identified novel classes of KDR inhibitors. This review presents structure activity relationships (SAR) of small molecule inhibitors of KDR, with an emphasis on the pharmacophore elements of the scaffolds employed. Binding hypotheses based on X-ray crystallographic analyses will also be described. Additionally, the efficacy of representative compounds in in vitro and in vivo models of tumor progression and angiogenesis are discussed.

Publication types

  • Review

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Angiogenesis Inhibitors / chemistry*
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Binding Sites
  • Binding, Competitive
  • Crystallography, X-Ray
  • Endothelial Growth Factors / metabolism
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Heterocyclic Compounds / chemistry*
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / pathology
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism


  • Angiogenesis Inhibitors
  • Endothelial Growth Factors
  • Enzyme Inhibitors
  • Heterocyclic Compounds
  • Adenosine Triphosphate
  • Vascular Endothelial Growth Factor Receptor-2