Structure-based discovery of a small non-peptidic Neuropilins antagonist exerting in vitro and in vivo anti-tumor activity on breast cancer model

Cancer Lett. 2014 Jul 28;349(2):120-7. doi: 10.1016/j.canlet.2014.04.004. Epub 2014 Apr 19.


Neuropilin-1/-2 (+33 NRPs), VEGF-A165 co-receptors, are over-expressed during cancer progression. Thus, NRPs targeted drug development is challenged using a multistep in silico/in vitro screening procedure. The first fully non-peptidic VEGF-A165/NRPs protein-protein interaction antagonist (IC50=34 μM) without effect on pro-angiogenic kinases has been identified (compound-1). This hit showed breast cancer cells anti-proliferative activity (IC50=0.60 μM). Compound-1 treated NOG-xenografted mice significantly exerted tumor growth inhibition, which is correlated with Ki-67(low) expression and apoptosis. Furthermore, CD31(+)/CD34(+) vessels are reduced in accordance with HUVEC-tube formation inhibition (IC50=0.20 μM). Taking together, compound-1 is the first fully organic inhibitor targeting NRPs.

Keywords: Fully organic inhibitors; Neuropilin; Protein–protein interaction; Tumor growth inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Disease Progression
  • Drug Evaluation, Preclinical
  • Female
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Humans
  • Ligands
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Models, Molecular
  • Molecular Docking Simulation
  • Neuropilins / antagonists & inhibitors*
  • Neuropilins / chemistry
  • Neuropilins / metabolism
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / metabolism
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Ligands
  • Neuropilins
  • Peptide Fragments
  • Small Molecule Libraries
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A (138-165)