J Biol Chem. 2003 Aug 19 [Epub ahead of print].
Bhat RV, Xue Y, Berg S, Hellberg (1) S, Ormo M, Nilsson Y, Radesater AC, Jerning E, Markgren PO, Borgegard T, Nylof M, Gimenez-Cassina A, Hernandez F, Lucas JJ, Diaz-Nido J, Avila J.
Research DMPK, AstraZeneca RD Sdertlje, Sdertlje 15185.
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 mM) or 26 other kinases demonstrating high specificity for GSK3.
We report the co-crystallisation 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 4-repeat tau protein.
AR-A014418 protects N2A neuroblastoma cells against cell death mediated by inhibition of the PI3K/PKB 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 Alzheimers 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.
PMID: 12928438 [PubMed – as supplied by publisher]