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    CHIR-98014
    CHIR-98014

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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 #: V0213
    CAS #: 252935-94-7 Purity ≥98%

    Description: CHIR-98014 (also known as CT-98024) is a novel, potent,  reversible, cell-permeable inhibitor of GSK-3 (glycogen synthase kinase-3) with potential anti-diabetic activity. It ATP-competitively inhibits GSK-3α/β with an IC50 of 0.65 nM/0.58 nM in cell-free assays, and is able to distinguish GSK-3 from its closest homologs Cdc2 and ERK2. When tested with insulin receptor-expressing CHO-IR cells or primary rat hepatocytes, CHIR-98014 stimulated the GS activity ratio as high as two- to three fold compared with basal in a dose dependent manner. Similarly, in isolated type 1 skeletal muscle from insulin-sensitive lean Zucker and from insulin-resistant ZDF rats, administration of CHIR-98014 activated GS activity ratio. 

    References:Diabetes. 2003 Mar;52(3):588-95; Br J Pharmacol. 2007 Nov;152(6):959-79.   

    Related CAS: 556813-39-9; 252935-94-7 (CHIR-98014 HCl) 

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    Molecular Weight (MW)

    486.31

    Formula

    C20H17Cl2N9O2

    CAS No.

    252935-94-7 (CHIR-98014); 

    Storage

    -20℃ for 3 years in powder form

    -80℃ for 2 years in solvent

    Solubility (In vitro)

    DMSO: 8 mg/mL (16.45 mM)

    Water: <1 mg/mL

    Ethanol: <1 mg/mL

    SMILES

     NC1=NC(NCCNC2=NC=C(N3C=CN=C3)C(C4=CC=C(Cl)C=C4Cl)=N2)=CC=C1[N+]([O-])=O

    Synonyms

     CT-98014; CT 98014; CT98014; CHIR 98014; CHIR-98014; CHIR98014; CHIR98014 HCl; CHIR-98014 hydrochloride;


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    In Vitro

    In Vitro activity: CHIR-98014 inhibits human GSK-3β with Ki of 0.87 nM. CHIR-98014 is very effective in preventing murine and rat GSK-3. Although CHIR-98014 acts as a simple competitive inhibitor of ATP binding, it displays from 500-fold to >1000-fold selectivity for GSK-3 versus 20 other protein kinases including Cdc2, ERK2, Tie-2 and KDR. CHIR-98014 prevents Cdc2 with IC50 of 3.7 μM. However, CHIR 98014 reveals similar ptoency against the highly homologous ɑ and β isoforms of GSK-3, it is noteworthy that it stronly discriminated between GSK-3 and its closest homologs CDC2 and ERK2. Exposure of insulin receptor-expressing CHO-IR cells or primary rat hepatocytes to increasing concentrations of inhibitor CHIR98014 results in a two- to three-fold stimulation of the GS activity ratio above basal. The concentrations of CHIR-98014 giving rise to half-maximal GS stimulation (EC50) is 106 nM and 107 nM for CHO-IR and rat hepatocytes, respectively.

     

    Kinase Assay: Polypropylene 96-well plates are filled with 300 μL/well buffer (50 mM tris HCl, 10 mM MgCl2, 1 mM EGTA, 1 mM dithiothreitol, 25 mM β-glycerophosphate, 1 mM NaF, 0.01% BSA, pH 7.5) containing kinase, peptide substrate, and any activators. CHIR-98014 or controls are added in 3.5 μL of DMSO, followed by 50 μL of ATP stock to yield a final concentration of 1 μM ATP in all cell-free assays. After incubation, triplicate 100-μL aliquots are transferred to Combiplate eight plates containing 100 μL/well 50 μM ATP and 20 mM EDTA. After 1 hour, the wells are rinsed five times with PBS, filled with 200 μL of scintillation fluid, sealed, left 30 min, and counted in a scintillation counter. All steps are performed at room temperature.

     

    Cell Assay: CHO-IR cells expressing human insulin receptor are grown to 80% confluence in Hamm’s F12 medium with 10% fetal bovine serum and without hypoxanthine. Trypsinized cells are seeded in 6-well plates at 1 × 106 cells/well in 2 mL of medium without fetal bovine serum. After 24 hours, medium is replaced with 1 mL of serum-free medium containing GSK-3 inhibitor CHIR 98014 or control (final DMSO concentration 0.1%) for 30 min at 37 °C. Cells are lysed by freeze/thaw in 50 mM tris (pH 7.8) containing 1 mM EDTA, 1 mM DTT, 100 mM NaF, 1 mM phenylmethylsulfonyl fluoride, and 25 μg/mL leupeptin (buffer A) and centrifuged 15 min at 4 °C/14000 g. The activity ratio of GS is calculated as the GS activity in the absence of glucose-6-phosphate divided by the activity in the presence of 5 mM glucose-6-phosphate.

    In Vivo

    GSK-3 inhibitor CHIR-98014 activates the GS activity ratio in isolated type I skeletal muscle from insulin-sensitive lean Zucker and from insulin-ressitant ZDF rats. Soleus muscle isolated from ZDF rats shows significant resistance to insulin for activation of GS but responded to 500 nM CHIR-98014 to the same extent (40% increase) as muscle from lean Zucker rats. Notably, GS activation by insulin plus CHIR-98014 is additive in muscle from lean Zucker rats and greater than additive in muscle from the ZDF rats. Total GS activity is not altered by either CHIR-98014 or insulin in these cells and muscles. Meanwhile, CHIR-98014 does not influence the insulin dose-response in muscle from lean animals. The reduction in hyperglycemia and improved glucose disposal are not limited to db/db mice and ZDF rats, as similar results are observed with ob/ob mice, diet-induced diabetic C57BL/6 mice, and glucose-intolerant SHHF rats treated with CHIR-98014. Additionally, CHIR-98014 decreases the phosphorylation (Ser396) of tau protein in the cortex and hippocampus of postnatal rats.

    Animal model

    db/db mice with 8-9 weeks

    Formulation & Dosage

    Formulated in 15% Captisol/citrate vehicle; 30 mg/kg; s.c.

    References

    Diabetes. 2003 Mar;52(3):588-95; Br J Pharmacol. 2007 Nov;152(6):959-79.


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

    CHIR-98014

    The aminopyrimidine GSK-3 inhibitor, CHIR98014, reduced tau phosphorylation in vivo.  2007 Nov;152(6):959-79.

    CHIR-98014

    CHIR98014, reduced tau phosphorylation in a dose-dependent manner in vivo.  2007 Nov;152(6):959-79.

    CHIR-98014

    Characterization of the postnatal rat model.  2007 Nov;152(6):959-79.Characterization of the postnatal rat model. Br J Pharmacol. 2007 Nov;152(6):959-79.


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