生物活性

• 靶点

  GSK-3α Ki:6.9nM

  GSK-3β Ki:31nM

• 描述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].

• 动物研究
  剂量	Mice[2] (p.o.): 15 μmol/kg
  给药途径	p.o.
  动物药代数据	Animal Mice T1/2 7.1 h F 15 - 24%