Structure-based discovery of a small non-peptidic Neuropilins antagonist exerting in vitro and in vivo anti-tumor activity on breast cancer model
| Autor: | Rafika Jarray, Christiane Garbay, Olivier Hermine, Serena Pavoni, Françoise Raynaud, Brigitte Delhomme, Jean Luc Boucher, Réda Hadj-Slimane, Bertrand Leforban, Yves Lepelletier, Lucia Borriello, Matthieu Montes, Luc Demange, Wang-Qing Liu, Sylvie Dufour |
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| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Vascular Endothelial Growth Factor A Cancer Research Neuropilins In silico Drug Evaluation Preclinical Antineoplastic Agents Apoptosis Breast Neoplasms Mice Transgenic Mice SCID Pharmacology Biology Ligands Small Molecule Libraries Mice Structure-Activity Relationship Mice Inbred NOD In vivo Cell Line Tumor Human Umbilical Vein Endothelial Cells medicine Animals Humans Kinase Antagonist Cancer medicine.disease Xenograft Model Antitumor Assays Peptide Fragments In vitro Molecular Docking Simulation Oncology Disease Progression Female |
| Zdroj: | Cancer Letters. 349:120-127 |
| ISSN: | 0304-3835 |
| DOI: | 10.1016/j.canlet.2014.04.004 |
| Popis: | Neuropilin-1/-2 (+33 NRPs), VEGF-A 165 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-A 165 /NRPs protein–protein interaction antagonist (IC 50 = 34 μM) without effect on pro-angiogenic kinases has been identified (compound-1). This hit showed breast cancer cells anti-proliferative activity (IC 50 = 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 (IC 50 = 0.20 μM). Taking together, compound-1 is the first fully organic inhibitor targeting NRPs. |
| Databáze: | OpenAIRE |
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