A new chemical inhibitor of angiogenesis and tumorigenesis that targets the VEGF signaling pathway upstream of Ras

Abstract

// Agnès Desroches-Castan 1, 2, 3 , Delphine Quélard 1, 2, 3, 4 , Martine Demeunynck 2, 5 , Jean-François Constant 2, 6 , Chongling Dong 2, 6 , Michelle Keramidas 2, 7 , Jean-Luc Coll 2, 7 , Caroline Barette 2, 3, 8 , Laurence Lafanechère 2, 3, 7 , Jean-Jacques Feige 1, 2, 3 1 Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1036, Biology of Cancer and Infection, Grenoble, F-38054, France 2 Univ. Grenoble-Alpes, Department of Chemistry, Biology and Health Sciences, Grenoble, F-38000, France 3 Commissariat à l'Energie Atomique (CEA), DSV/iRTSV, Grenoble, F-38054, France 4 Janssen, Pharmaceutical Companies of Johnson and Johnson, Issy-les-Moulineaux, F-92130, France 5 Centre National de la Recherche Scientifique (CNRS), UMR 5063, Department of Molecular Pharmacochemistry, Grenoble, F-38041, France 6 Centre National de la Recherche Scientifique (CNRS), UMR 5250, Department of Molecular Chemistry, Grenoble, F-38041, France 7 Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 823, Albert Bonniot Research Center, La Tronche, F-38700, France 8 Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1038, Large Scale Biology, Grenoble, F-38054, France Correspondence to: Jean-Jacques Feige, e-mail: jean-jacques.feige@cea.fr Keywords: angiogenesis, chemical library, VEGF signaling, drug development Received: September 25, 2014      Accepted: December 19, 2014      Published: January 23, 2015 ABSTRACT The efficacy of anti-angiogenic therapies on cancer patients is limited by the emergence of drug resistance, urging the search for second-generation drugs. In this study, we screened an academic chemical library (DCM, University of Grenoble-Alpes) and identified a leader molecule, COB223, that inhibits endothelial cell migration and proliferation. It inhibits also Lewis lung carcinoma (LLC/2) cell proliferation whereas it does not affect fibroblast proliferation. The anti-angiogenic activity of COB223 was confirmed using several in vitro and in vivo assays. In a mouse LLC/2 tumor model, ip administration of doses as low as 4 mg/kg COB223 efficiently reduced the tumor growth rate. We observed that COB223 inhibits endothelial cell ERK1/2 phosphorylation induced by VEGF, FGF-2 or serum and that it acts downstream of PKC and upstream of Ras. This molecule represents a novel anti-angiogenic and anti-tumorigenic agent with an original mechanism of action that deserves further development as an anti-cancer drug.