Tideglusib is an irreversibleGSK-3 inhibitor with IC50 of 5 nM and 60 nM for GSK-3βWT (1 h preincubation) and GSK-3βC199A (1 h preincubation), respectively.
GSK-3 (Glycogen synthase kinase 3) is a serine/threonine protein kinase, consisting of GSK-3 and 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/-catenin signaling[2][3]. Tideglusib is a thiadiazolidinedione-derived GSK-3 inhibitor with Ki value of 60nM (calculated by double ATP and inhibitor titrations) and can inhibit GSK-3 with IC50 value of 105nM (measured by enzymatic assays of human recombinant GSK-3)[1]. Tideglusib can increase the level of phosphorylated GSK3-S9, as well as decreased the level of phosphorylated tau, in a dose or time dependent manner in GSC11 cells treated on dose of 0-10uM or in 0-6h[4]. Tideglusib shows neuroprotection against hypoxic-ischemic brain injury in neonatal mice. Intraperitoneal administration of tideglusib (5 mg/kg) 20 min prior to the onset of ischemia can reduce cerebral infarct volume at both 24 h and 7 days after hypoxic-ischemic injury[5]. Several clinical studies on neurological diseases, including two phase 2 studies of Alzheimer's disease, have been completed (see in https://www.clinicaltrials.gov/).
作用机制
Tideglusib is a thiadiazolidinedione-derived non-ATP competitive inhibitor of GSK3.
Tideglusib 动物研究
Dose
Mice: min = 50 mg/kg[7], max = 200 mg/kg p.o.[8]; 5 mg/kg i.p.[5]
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