Author/Authors :
Borriello، نويسنده , , Lucia and Montès، نويسنده , , Matthieu and Lepelletier، نويسنده , , Yves and Leforban، نويسنده , , Bertrand and Liu، نويسنده , , Wang-Qing and Demange، نويسنده , , Luc and Delhomme، نويسنده , , Brigitte and Pavoni، نويسنده , , Serena and Jarray، نويسنده , , Rafika and Boucher، نويسنده , , Jean Luc and Dufour، نويسنده , , Sylvie and Hermine، نويسنده , , Olivier and Garbay، نويسنده , , Christiane and Hadj-Slimane، نويسنده , , Réda and Raynaud، نويسنده , , Françoise، نويسنده ,
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.
Keywords :
Neuropilin , Protein–protein interaction , Tumor growth inhibition , Fully organic inhibitors
