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Anticancer Activity of BIM-46174, a New Inhibitor of the Heterotrimeric G/Gß Protein Complex

¹ IPSEN-Institut Henri Beaufour, Les Ulis, France; ² Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland; ³ Institut National de la Sante et de la Recherche Medicale U673, Université Pierre and Marie Curie, Paris-VI, Molecular and Clinical Oncology of Human Solid Tumors, Hôpital Saint-Antoine, Paris, France; ⁴ Laboratory of Experimental Cancerology, University Hospital, Gent, Belgium; and ⁵ IPSEN Albert Beaufour Research Institute, Milford, Massachusetts

Requests for reprints: Grégoire P. Prévost, IPSEN-Institut Henri Beaufour, 5 Avenue du Canada, 91966 Les Ulis, France. Phone: 33-1-60-92-20-00; Fax: 33-1-69-07-38-02; E-mail: gregoire.prevost{at}ipsen.com.

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 (Gs), (b) calcium release (Gq), and (c) cancer cell invasion by Wnt-2 frizzled receptors and high-affinity neurotensin receptors (Go/i and Gq). 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. (Cancer Res 2006; 66(18): 9227-34)

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