Gsk3 inhibitors: development and therapeutic potential

KEY POINTS * In the late 1970s, glycogen synthase kinase-3 (GSK3) was identified as a protein kinase that inactivates glycogen synthase, but was ignored as a drug target by the

pharmaceutical industry until the mid-1990s, when its role in insulin signal transduction was clarified. * Several potent inhibitors of GSK3 were identified in the late 1990s, and cell-based

assays using these compounds indicated that they might have therapeutic potential for the treatment of diabetes. During the past year or so, very potent and more specific inhibitors of GSK3

have been introduced. * GSK3 inhibitors have now been shown to be effective in normalizing blood glucose levels in animal models of type 2 diabetes, with their effects seeming to occur

primarily through an increase in hepatic glycogen synthesis and a decrease in hepatic gluconeogenesis. * GSK3 inhibitors might also have potential for neurodegenerative disorders, such as

Alzheimer's disease. For example, there is recent evidence that GSK3 increases the production of β-amyloid — which has a key role in the pathogenesis of Alzheimer's disease — and

that inhibition of GSK3 might reduce β-amyloid levels. ABSTRACT Glycogen synthase kinase-3 (GSK3) was initially identified more than two decades ago as an enzyme involved in the control of

glycogen metabolism. In recent years it has been shown to have key roles in regulating a diverse range of cellular functions, which have prompted efforts to develop GSK3 inhibitors as

therapeutics. Here, we describe the biology of GSK3 relevant to its potential as a target for diabetes and neurodegenerative diseases, and discuss progress in the development of GSK3

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customer support SIMILAR CONTENT BEING VIEWED BY OTHERS GSK-3: A MULTIFACETED PLAYER IN ACUTE LEUKEMIAS Article 02 April 2021 EXPLORING NOVEL AND POTENT GLYCOGEN SYNTHASE KINASE-3Β

INHIBITORS THROUGH SYSTEMATIC DRUG DESIGNING APPROACH Article Open access 03 February 2025 THE ALDOLASE INHIBITOR ALDOMETANIB MIMICS GLUCOSE STARVATION TO ACTIVATE LYSOSOMAL AMPK Article

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Dundee, Dundee, DD1 5EH, UK Philip Cohen * MRC Laboratory of Molecular Biology, Cambridge, CB2 2QH, UK Michel Goedert Authors * Philip Cohen View author publications You can also search for

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ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RELATED LINKS RELATED LINKS DATABASES ENTREZ GENE APC APH1 APP axin β-catenin BACE dishevelled

FRAT glycogen synthase GSK3 huntingtin IRS1 nicastrin PEN2 presenilin ONLINE MENDELIAN INHERITANCE IN MAN Alzheimer's disease familial frontotemporal dementia Huntington's disease

Pick's disease progressive supranuclear palsy GLOSSARY * ZUCKER DIABETIC FATTY (ZDF) RAT A rodent with both a mutant, functionally deficient leptin receptor and a genetic defect that

predisposes it to diabetes, as it becomes obese and lipid accumulates in the pancreatic islets. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Cohen,

P., Goedert, M. GSK3 inhibitors: development and therapeutic potential. _Nat Rev Drug Discov_ 3, 479–487 (2004). https://doi.org/10.1038/nrd1415 Download citation * Issue Date: 01 June 2004

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