Inhibition of Heterotrimeric G Protein Signaling by a Small Molecule Acting on Gα Subunit

Abstract

The simultaneous activation of many distinct G proteincoupled receptors (GPCRs) and heterotrimeric G proteins play a major role in various pathological conditions. Pan-inhibition of GPCR signaling by small molecules thus represents a novel strategy to treat various diseases. To better understand such therapeutic approach, we have characterized the biomolecular target of BIM-46187, a small molecule pan-inhibitor of GPCR signaling. Combining bioluminescence and fluorescence resonance energy transfer techniques in living cells as well as in reconstituted receptor-G protein complexes, we observed that, by direct binding to the G␣ subunit, BIM-46187 prevents the conformational changes of the receptor-G protein complex associated with GPCR activation. Such a binding prevents the proper interaction of receptors with the G protein heterotrimer and inhibits the agonist-promoted GDP/GTP exchange. These observations bring further evidence that inhibiting G protein activation through direct binding to the G␣ subunit is feasible and should constitute a new strategy for therapeutic intervention.

Constitutive Activity of Serotonin2C Receptors at G Protein-Independent Signaling: Modulation by RNA Editing and Antidepressants

“…In contrast, BIM-46,187 inhibited both constitutive and 5-HT-elicited IP production (Fig. 5B), consistent with previous observations made in transfected cells (Ayoub et al, 2009). Moreover, exposure to SB206,553 (1 M), which inhibited basal IP formation, did not further reduce the level of IPs in BIM-46,187-treated choroid plexuses.…”

“…5A). Neither basal nor 5-HT-elicited ERK1/2 phosphorylation was affected by treatment of choroid plexus with BIM-46,187 (10 M), an inhibitor of GPCR signaling mediated by all heterotrimeric G protein families (Ayoub et al, 2009). In contrast, BIM-46,187 inhibited both constitutive and 5-HT-elicited IP production (Fig.…”

Autocrine Induction of Invasive and Metastatic Phenotypes by the MIF-CXCR4 Axis in Drug-Resistant Human Colon Cancer Cells

“…In agreement, the 5F7 invasive phenotype was alleviated by the Gαi inhibitor PTx, the new G protein signaling inhibitor BIM-46187 targeting Gα subunits downstream activated G protein-coupled receptor (GPCR; ref. 25), and by pharmacologic inhibitors targeting PLCβ (U73122) and PKA (KT5720). In addition, collagen invasion was inhibited by pharmacologic inhibitors targeting phosphoinositide-3-kinase (wortmannin), PKC (Gö6976), and the Rho-ROCK axis (C3T and Y27632).…”

Identification of a GαGβγ, AKT and PKCα signalome associated with invasive growth in two genetic models of human breast cancer cell epithelial-to-mesenchymal transition

“…Of note, GPR30 is now considered as a marker of the metastatic potential in BC (15,16). Consistently, GPR signaling pathways are now considered in targeted therapies against cancer, as recently exemplified by the discovery of small molecule inhibitors targeting Gα or Gβγ subunits (17)(18)(19)(20)(21).…”