title: Structure-based discovery of a small non-peptidic Neuropilins antagonist exerting in vitro and in vivo anti-tumor activity on breast cancer model.
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.
authors.affiliation: 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.
authors.forename: Lucia
authors.initials: L
authors.lastname: Borriello
authors.affiliation: Conservatoire National des Arts et Métiers, Chaire de Bioinformatique, Laboratoire Génomique, Bioinformatique et Applications, EA 4627, 292 rue Saint Martin, 75003 Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Montès
authors.affiliation: 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.
authors.forename: Yves
authors.initials: Y
authors.lastname: Lepelletier
authors.affiliation: 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.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Leforban
authors.affiliation: 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.
authors.forename: Wang-Qing
authors.initials: WQ
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Luc
authors.initials: L
authors.lastname: Demange
authors.affiliation: CNRS FRE 3235, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Delhomme
authors.affiliation: 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.
authors.forename: Serena
authors.initials: S
authors.lastname: Pavoni
authors.affiliation: 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.
authors.forename: Rafika
authors.initials: R
authors.lastname: Jarray
authors.affiliation: 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.
authors.forename: Jean Luc
authors.initials: JL
authors.lastname: Boucher
authors.affiliation: UMR 144 CNRS-Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dufour
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.affiliation: 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.
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
authors.affiliation: Tragex Pharma, 29 Rue Marcel Dassault, 92100 Boulogne-Billancourt, France.
authors.forename: Réda
authors.initials: R
authors.lastname: Hadj-Slimane
authors.affiliation: 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.
authors.forename: Françoise
authors.initials: F
authors.lastname: Raynaud
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D008024:Ligands; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D039921:Neuropilins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D039921:Neuropilins; D010446:Peptide Fragments; D054852:Small Molecule Libraries; D042461:Vascular Endothelial Growth Factor A; C511613:vascular endothelial growth factor A (138-165)
keywords: Fully organic inhibitors; Neuropilin; Protein–protein interaction; Tumor growth inhibition