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

作者：Desroches Castan Agnes; Quelard Delphine; Demeunynck Martine; Constant Jean Francois; Dong Chongling; Keramidas Michelle; Coll Jean Luc; Barette Caroline; Lafanechere Laurence; Feige Jean Jacques^*

来源：Oncotarget, 2015, 6(7): 5382-5411.

DOI：10.18632/oncotarget.2979

• angiogenesis
• chemical library
• VEGF signaling
• drug development

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.

• 出版日期2015-3-10
• 单位中国地震局