Pharmacological inhibitors of glycogen synthase kinase 3

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Three closely related forms of glycogen synthase kinase 3 (GSK-3α, GSK-3β and GSK-3β2) 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-3β 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 β-catenin, contains many additional target sites for specific modulation of its activity.

Section snippets

Pharmacological inhibitors: diversity of structures and mechanism of action

It was nearly 50 years after the discovery of the unique properties of lithium in manic-depression illness (bipolar affective disorder) that GSK-3 was identified as one of its main targets 8, 9, 10. Since then, lithium has been used widely as a pharmacological inhibitor of GSK-3, despite the millimolar concentrations that are required to affect GSK-3 in living cells.

The definitive mood-stabilizing properties of lithium, the insulin-mimetic properties of GSK-3 inhibition and the GSK-3-dependent

The selectivity of inhibitors

Selectivity is a key issue when GSK-3 inhibitors are used as pharmacological tools to demonstrate the involvement of GSK-3 in a cellular process. By contrast, absolute selectivity is not necessarily the best approach when considering GSK-3 inhibitors as potential treatments for complex diseases in which multiple pathways are deregulated, because high selectivity could lead rapidly to resistance.

Because the ATP-binding pockets of GSK-3α and GSK-3β are similar, inhibitors that target these sites

GSK-3 inhibitors: diversity of applications

Based on knowledge of the literature, several therapeutic areas might benefit from the development of GSK-3 inhibitors (Figure 4). Obviously many of our suggestions are highly speculative. In addition, the potential toxicities and absorption, distribution, metabolism and excretion (ADME) properties of GSK-3 inhibitors could mitigate against their clinical use.

Concluding remarks

The existence of three closely related, non-interchangeable isoforms of GSK-3 (GSK-3α, GSK-3β and GSK-3β2), the multiple, sometimes apparently opposing, functions of GSK-3, and the poorly characterized selectivity, cell permeability and stability of pharmacological inhibitors of GSK-3 means that the development of therapeutically useful anti-GSK-3 drugs will not be easy. However, the partial success of lithium, the clear connection between dysregulation of GSK-3 and major human diseases, the

Acknowledgements

The work resulting in this publication was supported by grants MH40899 and DA10044 from the National Institutes of Health (P.G.), a grant from the Peter Jay Sharp Foundation (P.G.) and by the Ministère de la Recherche/INSERM/CNRS ’Molécules et Cibles Thérapeutiques’ Programme (L.M.). L.M.’s stay at the Rockefeller University was supported by the Rockefeller University, the CNRS and a NATO fellowship. We are thankful to Christian Doerig for critical reading of the manuscript.

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