Anticancer activity of BIM-46174, a new inhibitor of the heterotrimeric Galpha/Gbetagamma protein complex

Cancer Res. 2006 Sep 15;66(18):9227-34. doi: 10.1158/0008-5472.CAN-05-4205.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • Cysteine / analogs & derivatives*
  • Cysteine / pharmacology
  • Drug Screening Assays, Antitumor
  • Female
  • GTP-Binding Protein alpha Subunits / antagonists & inhibitors
  • GTP-Binding Protein alpha Subunits / metabolism
  • GTP-Binding Protein beta Subunits / antagonists & inhibitors
  • GTP-Binding Protein beta Subunits / metabolism
  • GTP-Binding Protein gamma Subunits / antagonists & inhibitors
  • GTP-Binding Protein gamma Subunits / metabolism
  • HL-60 Cells
  • Heterotrimeric GTP-Binding Proteins / antagonists & inhibitors*
  • Heterotrimeric GTP-Binding Proteins / metabolism
  • Humans
  • Imidazoles / pharmacology*
  • Mice
  • Neoplasm Invasiveness
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • BIM 46174
  • GTP-Binding Protein alpha Subunits
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Imidazoles
  • Heterotrimeric GTP-Binding Proteins
  • Cysteine