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

Lucia Borriello; Matthieu Montès; Yves Lepelletier; Bertrand Leforban; Wang-Qing Liu; Luc Demange; Brigitte Delhomme; Serena Pavoni; Rafika Jarray; Jean Luc Boucher; Sylvie Dufour; Olivier Hermine; Christiane Garbay; Réda Hadj-Slimane; Françoise Raynaud

doi:10.1016/j.canlet.2014.04.004

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.

Authors

Affiliations

¹ UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France.
² Conservatoire National des Arts et Métiers, Chaire de Bioinformatique, Laboratoire Génomique, Bioinformatique et Applications, EA 4627, 292 rue Saint Martin, 75003 Paris, France.
³ INSERM UMR 1163, Laboratory of cellular and molecular basis of normal hematopoiesis and hematological disorders: therapeutical implications, 24 boulevard Montparnasse, 75015 Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, 24 boulevard Montparnasse, 75015 Paris, France; CNRS ERL 8254, 24 boulevard Montparnasse, 75015 Paris, France.
⁴ CNRS FRE 3235, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France.
⁵ UMR 144 CNRS-Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
⁶ Tragex Pharma, 29 Rue Marcel Dassault, 92100 Boulogne-Billancourt, France.
⁷ UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France. Electronic address: francoise.raynaud@parisdescartes.fr.

PMID: 24752068
DOI: 10.1016/j.canlet.2014.04.004

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.

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

Substances

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