Pharmacological inhibitors of glycogen synthase kinase 3.
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.
Meijer
Laurent
L
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, NY 10021-6399, USA. meijer@sb-roscoff.fr
Flajolet
Marc
M
Greengard
Paul
P
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D009422:Nervous System Diseases / Q000188:drug therapy; D010272:Parasitic Diseases / Q000188:drug therapy; D015398:Signal Transduction; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3