Inhibition of heterotrimeric G protein signaling by a small molecule acting on Galpha subunit

J Biol Chem. 2009 Oct 16;284(42):29136-45. doi: 10.1074/jbc.M109.042333. Epub 2009 Jul 31.


The simultaneous activation of many distinct G protein-coupled 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 Galpha 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 Galpha subunit is feasible and should constitute a new strategy for therapeutic intervention.

MeSH terms

  • Animals
  • COS Cells
  • Calcium / metabolism
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Cyclic AMP / metabolism
  • Cyclohexanes / pharmacology
  • DNA, Complementary / metabolism
  • GTP-Binding Protein alpha Subunits / metabolism*
  • Gene Expression Regulation*
  • Heterotrimeric GTP-Binding Proteins / metabolism*
  • Humans
  • Models, Biological
  • Plasmids / metabolism
  • Pyrazines / pharmacology
  • Signal Transduction


  • 7-(2-amino-1-oxo-3-thio-propyl)-8-cyclohexylmethyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-(1,2a)-pyrazine dimer, hydrochloride
  • Cyclohexanes
  • DNA, Complementary
  • GTP-Binding Protein alpha Subunits
  • Pyrazines
  • Cyclic AMP
  • Heterotrimeric GTP-Binding Proteins
  • Calcium