TY - JOUR
T1 - Anticancer activity of BIM-46174, a new inhibitor of the heterotrimeric Gα/Gβγ protein complex
AU - Prévost, Grégoire P.
AU - Lonchampt, Marie O.
AU - Holbeck, Susan
AU - Attoub, Samir
AU - Zaharevitz, Daniel
AU - Alley, Mike
AU - Wright, John
AU - Brezak, Marie C.
AU - Coulomb, Hélène
AU - Savola, Ann
AU - Huchet, Marion
AU - Chaumeron, Sophie
AU - Nguyen, Quang Dé
AU - Forgez, Patricia
AU - Bruyneel, Erik
AU - Bracke, Mark
AU - Ferrandis, Eric
AU - Roubert, Pierre
AU - Demarquay, Daniéle
AU - Gespach, Christian
AU - Kasprzyk, Philip G.
PY - 2006/9/15
Y1 - 2006/9/15
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=33749473192&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-05-4205
DO - 10.1158/0008-5472.CAN-05-4205
M3 - Article
C2 - 16982767
AN - SCOPUS:33749473192
SN - 0008-5472
VL - 66
SP - 9227
EP - 9234
JO - Cancer Research
JF - Cancer Research
IS - 18
ER -