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    AZD2858
    AZD2858

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0219
    CAS #: 486424-20-8Purity ≥98%

    Description: AZD2858 is a novel, potent, orally bioactive, and selective GSK-3 (glycogen synthase kinase-3) inhibitor with the potential to be used in fracture healing. It inhibits GSK-3 with an IC50 of 68 nM. It can activate the Wnt signaling, and increase bone mass in rats. Treatment rats with AZD2858 orally increased trabecular bone mass in a dose-dependent way after a two-week treatment. The significant effect was also seen at cortical sites. Both vertebral compression strength and diaphyseal strength of femora increased in biomechanical testing.

    References: Bone. 2012 Mar;50(3):619-27;Toxicol Appl Pharmacol. 2013 Oct 15;272(2):399-407; Bone. 2013 May;54(1):126-32.

    Related CAS #: 2108876-05-5 (HCl); 486424-20-8 (free base); 486424-21-9 (xHCl)

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    Molecular Weight (MW)

    453.52

    Formula

    C21H23N7O3S

    CAS No.

    486424-20-8

    Storage

    -20℃ for 3 years in powder form

    -80℃ for 2 years in solvent

    Solubility (In vitro)

    DMSO: 7 mg/mL (15.43 mM)     

    Water: <1 mg/mL

    Ethanol: <1 mg/mL

    Solubility (In vivo)

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

    Synonyms

    AZD-2858; AZD2858; AZD 2858

    Chemical Name: 3-amino-6-[4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl]-N-3-pyridinyl-2-pyrazinecarboxamid

    InChi Key: FHCSBLWRGCOVPT-UHFFFAOYSA-N

    InChi Code: InChI=1S/C21H23N7O3S/c1-27-9-11-28(12-10-27)32(30,31)17-6-4-15(5-7-17)18-14-24-20(22)19(26-18)21(29)25-16-3-2-8-23-13-16/h2-8,13-14H,9-12H2,1H3,(H2,22,24)(H,25,29)

    SMILES Code: NC1=NC=C(C2=CC=C(S(N3CCN(C)CC3)(=O)=O)C=C2)N=C1C(NC4=CC=CN=C4)=O



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    In Vitro

    In vitro activity: AZD2858 is a selective GSK-3 inhibitor with an IC50 of 68 nM, inhibits tau phosphorylation at the S396 site, activates Wnt signaling pathway. AZD2858 treatment (1 μM, 12 h) on primary isolated human osteoblast-like cells results in a 3-fold increase of β-catenin levels. AZD2858 causes β-catenin stabilisation in human and rat mesenchymal stem cells, stimulates hADSC commitment towards osteoblasts and osteogenic mineralisation in vitro.

     

    Kinase Assay: Tau phosphorylation assay: NIH-3T3 cells expressing 4-repeat Tau are used to assess functional activity of AZD2858 in vitro. The cells are grown in DMEM media and 2 mM L-glut, and 10% HiFCS, and plated at a concentration of 6×105 cells/well in 6-well plates. In each experiment, AZD2858 is dosed in triplicates at a concentration of 1, 10, 100, 500, 1000, 2000 and 10,000 nM. Cells are treated for 4 h prior to cell lysis using 100 μL ice cold lysis buffer (0.5% NP-40, 10 mM Tris, pH 7.2, 150 mM NaCl, 2 mM EDTA). A suspension is made with addition of protease and phosphatase inhibitors: 50 mM NaF, 0.2 mM NaVO4 and Cocktail Protease inhibitors. The solution is then snap frozen at − 80 °C for at least 1 h, before thawing on ice and lysate clarification by centrifugation, followed by Western blot according to standard protocols. After blocking, the blots are exposed to the primary antibody, Phospho-Ser396-tau (1:1000) over night, washed and incubated with the secondary antibody (donkey anti-rabbit, 1:5000), followed by a final wash. For re-probing, the primary antibody Tau5 (1:200) and the secondary horseradish peroxidase linked antibody (sheep anti-mouse, 1:10000) are used. All blots are developed using ECL Western blot detection reagents, Kodak X-ray films, quantified using densitometric analysis, and the ratio of S396 tau to total tau (tau5) is calculated.

     

    Cell Assay: Human adipose derived stem cells and rat MSCs (isolated from bone marrow of Sprague Dawley rats at less than 8 weeks after gestation) are cultured in a basal media of DMEM containing 5% FBS and 2 mM GlutaMax. Cells are seeded in basal media into 96-well plates (3–5000 cells/well) for 18 h before treatment with AZD2858 (0.3 nM to 20 mM). After 24 h, β-catenin stabilisation is measured.

    In Vivo

    In rats, oral AZD2858 treatment causes a dose-dependent increase in trabecular bone mass compared to control after a two-week treatment with a maximum effect at a dose of 20 mg/kg once daily (total BMC: 172% of control). A small but significant effect is also seen at cortical sites (total BMC: 111% of control). AZD285 treatment (30 μmol/kg) on rats daily for up to 3 weeks shows an increase in both mineral density (of 28% at 2 weeks and 38% at 3 weeks) and mineral content (of 81% at 2 weeks and 93% at 3 weeks) in the calluses. AZD285 treatment makes the fractures heals more rapidly, with a bony callus without an obvious endochondral component. AZD2858 produces time-dependent changes in serum bone turnover biomarkers and increases bone mass over 28 days exposure in rats. After 7 days, AZD2858 increases the bone formation biomarker P1NP, and reduces the resorption biomarker TRAcP-5b, indicating increased bone anabolism and reduced resorption in rats.

    Animal model

    Rat

    Formulation & Dosage

    Dissolved in water adjusted to pH 3.5 ; 30 mg/kg; Oral gavage

    References

    Bone. 2012 Mar;50(3):619-27;Toxicol Appl Pharmacol. 2013 Oct 15;272(2):399-407; Bone. 2013 May;54(1):126-32.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    AZD2858

    Expression of TAZ and Osterix, markers of commitment to osteoblastogenesis in human ADSC. Toxicol Appl Pharmacol. 2013 Oct 15;272(2):399-407

     

    AZD2858

    Time course of serum bone turnover biomarkers and femur histopathology changes with AZD2858 dosed orally for 3, 7, 14, 21 or 28 days


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