Pharmacological inhibitors of glycogen synthase kinase 3
Résumé
Three closely related forms of glycogen synthase kinase 3 (GSK-3alpha, GSK-3beta and GSK-3beta2) have a major role in Wnt and Hedgehog signaling pathways and regulate the cell-division cycle, stem-cell renewal and differentiation, apoptosis, circadian rhythm, transcription and insulin action. A large body of evidence supports speculation that pharmacological inhibitors of GSK-3 could be used to treat several diseases, including Alzheimer's disease and other neurodegenerative diseases, bipolar affective disorder, diabetes, and diseases caused by unicellular parasites that express GSK-3 homologues. The toxicity, associated side-effects and concerns regarding the absorption, distribution, metabolism and excretion of these inhibitors affect their clinical potential. More than 30 inhibitors of GSK-3 have been identified. Seven of these have been co-crystallized with GSK-3beta and all localize within the ATP-binding pocket of the enzyme. GSK-3, as part of a multi-protein complex that contains proteins such as axin, presenilin and beta-catenin, contains many additional target sites for specific modulation of its activity.
Mots clés
Animals Cell Differentiation/drug effects Diabetes Mellitus
Type 2/drug therapy Enzyme Inhibitors/chemistry/*pharmacology/therapeutic use Glycogen Synthase Kinase 3/*antagonists & inhibitors/chemistry Humans Neoplasms/drug therapy Nervous System Diseases/drug therapy Parasitic Diseases/drug therapy Research Support
Non-U.S. Gov't Research Support
U.S. Gov't
P.H.S. Signal Transduction Stem Cells/drug effects/pathology Structure-Activity Relationship