生物活性

• 靶点	GSK-3 IC50:68nM

• 描述Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. In mammals GSK-3 is encoded by two paralogous genes, GSK-3α and GSK-3β. GSK-3 is active in a number of central intracellular signaling pathways, including cellular proliferation, migration, glucose regulation, and apoptosis^[3]. AZD-2858, known as a GSK-3 inhibitor, had potency at both GSK-3β and GSK-3α enzymes with K_i value of 5nMand IC₅₀ value of 0.9nM, respectively, both of which were measured by ATP assay ^[4]. In vitro, treatment of primary isolated human osteoblast-like cells with 1μM AZD2858 for 12h showed a significant increase of β-catenin, and the IC₅₀ is 68nM for inhibition of tau phosphorylation by AZD2858 in 4-repeat-tau 3T3 cells ^[5]. Moreover, Western blotting result demonstrated that AZD-2858 inhibited tau phosphorylation in the transfected 3T3 fibroblasts in a dose-dependent fashion with increasing concentrations (100 nM to 50 μM) , exhibiting IC₅₀ value of 76nM ^[6]. Both the relative protein expression of the osteogenic markers TAZ and osterix following treatment with 6 nM to 20 μM of AZD2858 for 18h were increased in hADSC, demonstrating inhibition of GSK-3 stimulated osteoblastogenesis by AZD-2858. In addition, incubation of hADSC with 200nM AZD2858 for 26 days led to a marked increase in osteogenic mineralisation relative to DMSO vehicle control, indicating that inhibition of GSK-3 enhances osteogenic differentiation of hADSC^[4]. One In vivo study showed that oral gavage with AZD2858 (30 μmol/kg/day) produced time-dependent changes in serum bone turnover biomarkers and increased bone mass over 28 days exposure both in Female Han Wistar and Sprague–Dawley rats^[4], while the other one suggested that oral administration with AZD2858 to female Sprague Dawley rats caused a dose-dependent increase in trabecular bone mass compared to control group after a two-week treatment with a maximum effect at a dose of 20 mg/kg once daily ^[7]. Both in vivo studies revealed that AZD2858 may prove effective as an anabolic strategy in the treatment of diseases characterized by low bone mass.
• 作用机制AZD2858 binds to GSK-3 kinase to inhibit the formation of axin/GSK-3/APC-complex in Wnt-signaling pathway thereby stabilizing β-catenin to accumulate in the cytoplasm and translocate into the nucleus where it activates transcription ^[5].

• 动物研究
  剂量	Rat: 0.2 mg/kg - 20 mg/kg[3] (p.o.) Mice: 30 mg/kg[4] (s.c., BID)
  给药途径	p.o., s.c.