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Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418.

Abstract
Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease. We report the characterization of a GSK3 inhibitor, AR-A014418, which inhibits GSK3 (IC50 = 104 +/- 27 nM), in an ATP-competitive manner (Ki = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 > 100 microM) or 26 other kinases demonstrating high specificity for GSK3. We report the co-crystallization of AR-A014418 with the GSK3beta protein and provide a description of the interactions within the ATP pocket, as well as an understanding of the structural basis for the selectivity of AR-A014418. AR-A014418 inhibits tau phosphorylation at a GSK3-specific site (Ser-396) in cells stably expressing human four-repeat tau protein. AR-A014418 protects N2A neuroblastoma cells against cell death mediated by inhibition of the phosphatidylinositol 3-kinase/protein kinase B survival pathway. Furthermore, AR-A014418 inhibits neurodegeneration mediated by beta-amyloid peptide in hippocampal slices. AR-A014418 may thus have important applications as a tool to elucidate the role of GSK3 in cellular signaling and possibly in Alzheimer's disease. AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5.
AuthorsRatan Bhat, Yafeng Xue, Stefan Berg, Sven Hellberg, Mats Ormö, Yvonne Nilsson, Ann-Cathrin Radesäter, Eva Jerning, Per-Olof Markgren, Thomas Borgegård, Martin Nylöf, Alfredo Giménez-Cassina, Félix Hernández, Jose J Lucas, Javier Díaz-Nido, Jesús Avila
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 46 Pg. 45937-45 (Nov 14 2003) ISSN: 0021-9258 [Print] United States
PMID12928438 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Enzyme Inhibitors
  • Peptides
  • Thiazoles
  • tau Proteins
  • N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea
  • Adenosine Triphosphate
  • Urea
  • Cyclin-Dependent Kinase 5
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • CDK5 protein, human
  • Cdk2 protein, mouse
  • Cdk5 protein, mouse
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • Glycogen Synthase Kinase 3
Topics
  • Adenosine Triphosphate (chemistry, metabolism)
  • Animals
  • CDC2-CDC28 Kinases (metabolism)
  • Cell Death
  • Cell Line, Tumor
  • Cell Survival
  • Crystallography, X-Ray
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 5
  • Cyclin-Dependent Kinases (metabolism)
  • Dose-Response Relationship, Drug
  • Electrons
  • Enzyme Inhibitors (pharmacology)
  • Glycogen Synthase Kinase 3 (antagonists & inhibitors)
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Mice
  • Models, Chemical
  • Models, Molecular
  • NIH 3T3 Cells
  • Neurons (metabolism)
  • Peptides (chemistry)
  • Protein Binding
  • Signal Transduction
  • Thiazoles (chemistry, metabolism)
  • Urea (analogs & derivatives, chemistry, metabolism)
  • tau Proteins (chemistry)

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