Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418.
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.
Bhat
Ratan
R
AstraZeneca R&D, 15185 Södertälje, Sweden, AstraZeneca R&D, 43183 Mölndal, Sweden. ratan.bhat@astrazeneca.com
Xue
Yafeng
Y
Berg
Stefan
S
Hellberg
Sven
S
Ormö
Mats
M
Nilsson
Yvonne
Y
Radesäter
Ann-Cathrin
AC
Jerning
Eva
E
Markgren
Per-Olof
PO
Borgegård
Thomas
T
Nylöf
Martin
M
Giménez-Cassina
Alfredo
A
Hernández
Félix
F
Lucas
Jose J
JJ
Díaz-Nido
Javier
J
Avila
Jesús
J
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
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