Structure-based discovery of a small non-peptidic Neuropilins antagonist exerting in vitro and in vivo anti-tumor activity on breast cancer model |
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| Authors: | Lucia Borriello,Matthieu Montè s,Yves Lepelletier,Bertrand Leforban,Wang-Qing Liu,Luc Demange,Brigitte Delhomme,Serena Pavoni,Rafika Jarray,Jean Luc Boucher,Sylvie Dufour,Olivier Hermine,Christiane Garbay,Ré da Hadj-Slimane,Franç oise Raynaud |
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| Affiliation: | 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;4. Paris Descartes University–Sorbonne Paris Cité, Imagine Institute, 24 boulevard Montparnasse, 75015 Paris, France;5. CNRS ERL 8254, 24 boulevard Montparnasse, 75015 Paris, France;6. CNRS FRE 3235, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France;g UMR 144 CNRS-Institut Curie, 26 rue d’Ulm, 75005 Paris, France;h Tragex Pharma, 29 Rue Marcel Dassault, 92100 Boulogne-Billancourt, France |
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| 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-67low 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. |
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| Keywords: | Neuropilin Protein&ndash protein interaction Fully organic inhibitors Tumor growth inhibition |
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