Several agonists of G-protein coupled receptors (GPCR) are implicated in the promotion and progression of breast cancers.These include GPCR for estrogens (GPR30), endothelin, Frizzled/Wnt, SDF-1/MIF (CXCR4), LPA, neurotensin (NT-R1), Netrin/ adenosine A2B-R, and thrombin (PAR-1/EGF-R crosstalk).Recently, the new peptidomimetics BIM46174 and BIM-46187 were shown to inhibit the proliferation of several human cancer cell lines in culture (Cancer Res.66:9227, 2006 ; Nature Reviews Drug Discovery 5:894, 2006 ; J.Biol.Chem.284:29136, 2009).Accordingly, we found that these small molecules blocked cAMP generation and calcium translocations induced by several GPCR linked to the G-proteins Gas and Gaq.In coherence with these data, convergent molecular approaches revealed that BIM-46187 inhibits the physical interaction between ligand-activated GPCR and heterotrimeric G-proteins Ga-bg by selective binding with Ga subunits, to alleviate the GDP-GTP exchange induced by GPCR activation.