title: 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.
authors.affiliation: AstraZeneca R&D, 15185 Södertälje, Sweden, AstraZeneca R&D, 43183 Mölndal, Sweden. ratan.bhat@astrazeneca.com
authors.forename: Ratan
authors.initials: R
authors.lastname: Bhat
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Xue
authors.forename: Stefan
authors.initials: S
authors.lastname: Berg
authors.forename: Sven
authors.initials: S
authors.lastname: Hellberg
authors.forename: Mats
authors.initials: M
authors.lastname: Ormö
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Nilsson
authors.forename: Ann-Cathrin
authors.initials: AC
authors.lastname: Radesäter
authors.forename: Eva
authors.initials: E
authors.lastname: Jerning
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Markgren
authors.forename: Thomas
authors.initials: T
authors.lastname: Borgegård
authors.forename: Martin
authors.initials: M
authors.lastname: Nylöf
authors.forename: Alfredo
authors.initials: A
authors.lastname: Giménez-Cassina
authors.forename: Félix
authors.initials: F
authors.lastname: Hernández
authors.forename: Jose J
authors.initials: JJ
authors.lastname: Lucas
authors.forename: Javier
authors.initials: J
authors.lastname: Díaz-Nido
authors.forename: Jesús
authors.initials: J
authors.lastname: Avila
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004583:Electrons; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D015398:Signal Transduction; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism*; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D010455:Peptides; D013844:Thiazoles; D016875:tau Proteins; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D000255:Adenosine Triphosphate; D014508:Urea; D051360:Cyclin-Dependent Kinase 5; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495905:CDK5 protein, human; C495893:Cdk2 protein, mouse; C495906:Cdk5 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3