Anticancer activity of BIM-46174, a new inhibitor of the heterotrimeric Galpha/Gbetagamma protein complex.
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.
Prévost
Grégoire P
GP
IPSEN-Institut Henri Beaufour, Les Ulis, France. gregoire.prevost@ipsen.com
Lonchampt
Marie O
MO
Holbeck
Susan
S
Attoub
Samir
S
Zaharevitz
Daniel
D
Alley
Mike
M
Wright
John
J
Brezak
Marie C
MC
Coulomb
Hélène
H
Savola
Ann
A
Huchet
Marion
M
Chaumeron
Sophie
S
Nguyen
Quang-Dé
QD
Forgez
Patricia
P
Bruyneel
Erik
E
Bracke
Mark
M
Ferrandis
Eric
E
Roubert
Pierre
P
Demarquay
Danièle
D
Gespach
Christian
C
Kasprzyk
Philip G
PG
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
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