title: Anticancer activity of BIM-46174, a new inhibitor of the heterotrimeric Galpha/Gbetagamma protein complex.
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.
authors.affiliation: IPSEN-Institut Henri Beaufour, Les Ulis, France. gregoire.prevost@ipsen.com
authors.forename: Grégoire P
authors.initials: GP
authors.lastname: Prévost
authors.forename: Marie O
authors.initials: MO
authors.lastname: Lonchampt
authors.forename: Susan
authors.initials: S
authors.lastname: Holbeck
authors.forename: Samir
authors.initials: S
authors.lastname: Attoub
authors.forename: Daniel
authors.initials: D
authors.lastname: Zaharevitz
authors.forename: Mike
authors.initials: M
authors.lastname: Alley
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.forename: Marie C
authors.initials: MC
authors.lastname: Brezak
authors.forename: Hélène
authors.initials: H
authors.lastname: Coulomb
authors.forename: Ann
authors.initials: A
authors.lastname: Savola
authors.forename: Marion
authors.initials: M
authors.lastname: Huchet
authors.forename: Sophie
authors.initials: S
authors.lastname: Chaumeron
authors.forename: Quang-Dé
authors.initials: QD
authors.lastname: Nguyen
authors.forename: Patricia
authors.initials: P
authors.lastname: Forgez
authors.forename: Erik
authors.initials: E
authors.lastname: Bruyneel
authors.forename: Mark
authors.initials: M
authors.lastname: Bracke
authors.forename: Eric
authors.initials: E
authors.lastname: Ferrandis
authors.forename: Pierre
authors.initials: P
authors.lastname: Roubert
authors.forename: Danièle
authors.initials: D
authors.lastname: Demarquay
authors.forename: Christian
authors.initials: C
authors.lastname: Gespach
authors.forename: Philip G
authors.initials: PG
authors.lastname: Kasprzyk
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D018922:HL-60 Cells; D020962:Heterotrimeric GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D009361:Neoplasm Invasiveness; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C514995:BIM 46174; D044385:GTP-Binding Protein alpha Subunits; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D007093:Imidazoles; D020962:Heterotrimeric GTP-Binding Proteins; D003545:Cysteine