Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction

J Med Chem. 2010 Mar 11;53(5):2215-26. doi: 10.1021/jm901755g.


We report the molecular design and synthesis of EG00229, 2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRP1) and the structural characterization of NRP1-ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis studies localized VEGF-A binding in the NRP1 b1 domain and a peptide fragment of VEGF-A was shown to bind at the same site by NMR, providing the basis for small molecule design. Compound 2 demonstrated inhibition of VEGF-A binding to NRP1 and attenuated VEGFR2 phosphorylation in endothelial cells. Inhibition of migration of endothelial cells was also observed. The viability of A549 lung carcinoma cells was reduced by 2, and it increased the potency of the cytotoxic agents paclitaxel and 5-fluorouracil when given in combination. These studies provide the basis for design of specific small molecule inhibitors of ligand binding to NRP1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Humans
  • Inhibitory Concentration 50
  • Magnetic Resonance Spectroscopy
  • Mutagenesis, Site-Directed
  • Neuropilin-1 / antagonists & inhibitors
  • Neuropilin-1 / physiology*
  • Neuropilin-1 / ultrastructure
  • Peptide Fragments / chemical synthesis*
  • Peptide Fragments / genetics
  • Peptide Fragments / pharmacology
  • Peptide Fragments / ultrastructure
  • Phosphorylation
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / physiology*
  • Vascular Endothelial Growth Factor A / ultrastructure


  • Antineoplastic Agents
  • Peptide Fragments
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Neuropilin-1

Associated data

  • PDB/3I97