AZD1080 is a selective, orally active, brain permeable GSK3 inhibitor of GSK3α and GSK3β with Ki of 6.9 nM and 31 nM, respectively, shows > 14-fold selectivity against CDK2, CDK5, CDK1 and Erk2.
GSK-3 (Glycogen synthase kinase 3) is a serine/threonine protein kinase, consisting of GSK-3a and b subunit, which plays a key role in many different biological processes including tumorigenesis, cell survival, and developmental patterning. GSK-3 is constitutively active in non-stimulated cells and can negatively regulate canonical Wnt/b-catenin signaling[1]. AZD1080 is thiazole-derived inhibitor of GSK-3 with Ki values of 6.9 nM and 31 nM for GSK-3a and b, respectively, with >37-fold selectivity over CDKs. AZD1080 can inhibit tau phosphorylation through GSK3 in concentration-dependent manner, with IC50 value of 324 nM, in 3T3 fibroblasts engineered to stably express 4-repeat human tau. Similar effect of reduction on tau phosphorylation can also be observed in hippocampus of rats with acute oral administration of AZD1080 at 10 μmol/kg. Oral administration of AZD1080 at 15 μmol/kg can reverse MK-801-induced impairments in mouse model of cognition, as well as rescue LTP deficits in mouse hippocampal slices[2]. Treatment with AZD1080 on 1 - 4 μM can suppress cell proliferation, migration and invasion, as well as increase cell apoptosis and modulate NF-kB, Cyclin D1, MMP9, and P21 expression in endometrial cancer cells[3].
作用机制
AZD1080 binds in the ATP pocket of GSK3b where the oxindole ring system forms hydrogen bonds to the back-bone of the ATP pocket[2].
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