AZD2858

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Chemical Structure| 486424-20-8 同义名 : -
CAS号 : 486424-20-8
货号 : A128237
分子式 : C21H23N7O3S
纯度 : 99%
分子量 : 453.517
MDL号 : MFCD26397072
存储条件：

Pure form Keep in dark place,Inert atmosphere,Store in freezer, under -20°C

In solvent -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 12 mg/mL(26.46 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

30% PEG400+0.5% Tween80+5% propylene glycol+water 30 mg/mL suspension

生物活性
靶点

  • GSK-3

    GSK-3, IC50:68 nM
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 Ki 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].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.20mL

0.44mL

0.22mL

11.02mL

2.20mL

1.10mL

22.05mL

4.41mL

2.20mL
参考文献

[1]Gleyzer N, Scarpulla RC. Concerted Action of PGC-1-related Coactivator (PRC) and c-MYC in the Stress Response to Mitochondrial Dysfunction. J Biol Chem. 2016 Dec 2;291(49):25529-25541.

[2]Sisask G, Marsell R, et al. Rats treated with AZD2858, a GSK3 inhibitor, heal fractures rapidly without endochondral bone formation. Bone. 2013 May;54(1):126-32.

[3]GSK-3

[4] Gilmour PS, O'Shea PJ, Fagura M, Pilling JE, Sanganee H, Wada H, Courtney PF, Kavanagh S, Hall PA, Escott KJ. Human stem cell osteoblastogenesis mediated by novel glycogen synthase kinase 3 inhibitors induces bone formation and a unique bone turnover biomarker profile in rats. Toxicol Appl Pharmacol. 2013 Oct 15;272(2):399-407. doi: 10.1016/j.taap.2013.07.001. Epub 2013 Jul 18.

[5]Marsell R, Sisask G, Nilsson Y, Sundgren-Andersson AK, Andersson U, Larsson S, Nilsson O, Ljunggren O, Jonsson KB. GSK-3 inhibition by an orally active small molecule increases bone mass in rats. Bone. 2012 Mar;50(3):619-27. doi: 10.1016/j.bone.2011.11.007. Epub 2011 Nov 25.

[6] Berg S, Bergh M, Hellberg S, Högdin K, Lo-Alfredsson Y, Söderman P, von Berg S, Weigelt T, Ormö M, Xue Y, Tucker J, Neelissen J, Jerning E, Nilsson Y, Bhat R. Discovery of novel potent and highly selective glycogen synthase kinase-3β (GSK3β) inhibitors for Alzheimer's disease: design, synthesis, and characterization of pyrazines. J Med Chem. 2012 Nov 8;55(21):9107-19. doi: 10.1021/jm201724m. Epub 2012 Apr 27.

[7] Marsell R, Sisask G, Nilsson Y, Sundgren-Andersson AK, Andersson U, Larsson S, Nilsson O, Ljunggren O, Jonsson KB. GSK-3 inhibition by an orally active small molecule increases bone mass in rats. Bone. 2012 Mar;50(3):619-27. doi: 10.1016/j.bone.2011.11.007. Epub 2011 Nov 25.