Anticancer Activity of BIM-46174, a New Inhibitor of the Heterotrimeric Ga/Gßg Protein Complex.

Prevost, G.P., Lonchampt, M.O., Holbeck, S., Attoub, S., Zaharevitz, D., Alley, M., Wright, J., Brezak, M.C., Coulomb, H., Savola, A., Huchet, M., Chaumeron, S., Nguyen, Q.D., Forgez, P., Bruyneel, E., Bracke, M., Ferrandis, E., Roubert, P., Demarquay, D., Gespach, C., Kasprzyk, P.G.
Journal   Cancer Res.
Species  
Analytes Measured   Caspase-3 , PARP
Matrix Tested   HL-60 and NCI-H69 cell lysates
Year   2006
Volume   66
Page Numbers   9227-9234
Application   Phosphoproteins
Abstract
A large number of hormones and local agonists activating guanine-binding protein-coupled receptors (GPCR) play a major role in cancer progression. Here, we characterize the new imidazo-pyrazine derivative BIM-46174, which acts as a selective inhibitor of heterotrimeric G-protein complex. BIM-46174 prevents the heterotrimeric G-protein signaling linked to several GPCRs mediating (a) cyclic AMP generation (Galphas), (b) calcium release (Galphaq), and (c) cancer cell invasion by Wnt-2 frizzled receptors and high-affinity neurotensin receptors (Galphao/i and Galphaq). BIM-46174 inhibits the growth of a large panel of human cancer cell lines, including anticancer drug-resistant cells. Exposure of cancer cells to BIM-46174 leads to caspase-3-dependent apoptosis and poly(ADP-ribose) polymerase cleavage. National Cancer Institute COMPARE analysis for BIM-46174 supports its novel pharmacologic profile compared with 12,000 anticancer agents. The growth rate of human tumor xenografts in athymic mice is significantly reduced after administration of BIM-46174 combined with either cisplatin, farnesyltransferase inhibitor, or topoisomerase inhibitors. Our data validate the feasibility of targeting heterotrimeric G-protein functions downstream the GPCRs to improve anticancer chemotherapy.

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