Anticancer activity of BIM-46174, a new inhibitor of the heterotrimeric Gα/Gβγ protein complex

Grégoire P. Prévost, Marie O. Lonchampt, Susan Holbeck, Samir Attoub, Daniel Zaharevitz, Mike Alley, John Wright, Marie C. Brezak, Hélène Coulomb, Ann Savola, Marion Huchet, Sophie Chaumeron, Quang Dé Nguyen, Patricia Forgez, Erik Bruyneel, Mark Bracke, Eric Ferrandis, Pierre Roubert, Daniéle Demarquay, Christian GespachPhilip G. Kasprzyk

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56 Citations (Scopus)


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 (Gαs), (b) calcium release (Gαq), and (c) cancer cell invasion by Wnt-2 frizzled receptors and high-affinity neurotensin receptors (Gαo/i and Gαq). 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.

Original languageEnglish
Pages (from-to)9227-9234
Number of pages8
JournalCancer Research
Issue number18
Publication statusPublished - Sept 15 2006
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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