Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription

Chem Biol. 2000 Oct;7(10):793-803. doi: 10.1016/s1074-5521(00)00025-9.


Background: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase, the activity of which is inhibited by a variety of extracellular stimuli including insulin, growth factors, cell specification factors and cell adhesion. Consequently, inhibition of GSK-3 activity has been proposed to play a role in the regulation of numerous signalling pathways that elicit pleiotropic cellular responses. This report describes the identification and characterisation of potent and selective small molecule inhibitors of GSK-3.

Results: SB-216763 and SB-415286 are structurally distinct maleimides that inhibit GSK-3alpha in vitro, with K(i)s of 9 nM and 31 nM respectively, in an ATP competitive manner. These compounds inhibited GSK-3beta with similar potency. However, neither compound significantly inhibited any member of a panel of 24 other protein kinases. Furthermore, treatment of cells with either compound stimulated responses characteristic of extracellular stimuli that are known to inhibit GSK-3 activity. Thus, SB-216763 and SB-415286 stimulated glycogen synthesis in human liver cells and induced expression of a beta-catenin-LEF/TCF regulated reporter gene in HEK293 cells. In both cases, compound treatment was demonstrated to inhibit cellular GSK-3 activity as assessed by activation of glycogen synthase, which is a direct target of this kinase.

Conclusions: SB-216763 and SB-415286 are novel, potent and selective cell permeable inhibitors of GSK-3. Therefore, these compounds represent valuable pharmacological tools with which the role of GSK-3 in cellular signalling can be further elucidated. Furthermore, development of similar compounds may be of use therapeutically in disease states associated with elevated GSK-3 activity such as non-insulin dependent diabetes mellitus and neurodegenerative disease.

MeSH terms

  • Adenosine Triphosphate / antagonists & inhibitors
  • Adenosine Triphosphate / pharmacology
  • Aminophenols / pharmacology*
  • Binding, Competitive
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Line
  • Cytoskeletal Proteins / genetics
  • Diabetes Mellitus, Type 2 / drug therapy
  • Enzyme Activation / drug effects
  • Gene Expression Regulation / drug effects*
  • Genes, Reporter
  • Glycogen / biosynthesis
  • Glycogen / metabolism*
  • Glycogen Synthase / metabolism
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Humans
  • Indoles / pharmacology*
  • Kinetics
  • Liver / cytology
  • Liver / drug effects
  • Liver / enzymology
  • Liver / metabolism
  • Maleimides / pharmacology*
  • Molecular Structure
  • Neurodegenerative Diseases / drug therapy
  • Protein Kinases / metabolism
  • Recombinant Proteins
  • Signal Transduction / drug effects
  • Trans-Activators*
  • Transcription, Genetic / drug effects*
  • beta Catenin


  • 3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione
  • Aminophenols
  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • Indoles
  • Maleimides
  • Recombinant Proteins
  • SB 216763
  • Trans-Activators
  • beta Catenin
  • Adenosine Triphosphate
  • Glycogen
  • Glycogen Synthase
  • Protein Kinases
  • Glycogen Synthase Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3