Abstract
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.
Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Disease Progression
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Drug Evaluation, Preclinical
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Female
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Human Umbilical Vein Endothelial Cells / drug effects
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Humans
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Ligands
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Mice, Transgenic
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Models, Molecular
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Molecular Docking Simulation
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Neuropilins / antagonists & inhibitors*
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Neuropilins / chemistry
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Neuropilins / metabolism
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Peptide Fragments / antagonists & inhibitors
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Peptide Fragments / metabolism
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
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Vascular Endothelial Growth Factor A / antagonists & inhibitors
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Vascular Endothelial Growth Factor A / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Ligands
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Neuropilins
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Peptide Fragments
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Small Molecule Libraries
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A (138-165)