CHIR-98014

Alias: CT-98014; CT 98014; CT98014; CHIR 98014; CHIR-98014; CHIR98014;CHIR98014 HCl; CHIR-98014 hydrochloride
Cat No.:V0213 Purity: ≥98%
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.
CHIR-98014 Chemical Structure CAS No.: 252935-94-7
Product category: GSK-3
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of CHIR-98014:

  • CHIR-98024
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Purity & Quality Control Documentation

Purity: ≥98%

Product 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. With an IC50 of 0.65 nM/0.58 nM in cell-free assays, it ATP-competitively inhibits GSK-3/ and can distinguish GSK-3 from its closest homologs Cdc2 and ERK2. CHIR-98014 stimulated the GS activity ratio up to two to three fold in comparison to basal when tested with insulin receptor-expressing CHO-IR cells or primary rat hepatocytes in a dose-dependent manner. Similar to this, administration of CHIR-98014 activated the GS activity ratio in isolated type 1 skeletal muscle from insulin-sensitive lean Zucker and insulin-resistant ZDF rats.

Biological Activity I Assay Protocols (From Reference)
Targets
GSK-3β (IC50 = 0.58 nM); GSK-3α (IC50 = 0.65 nM); cdc2 (IC50 = 3700 nM)
ln Vitro
CHIR-98014 inhibits human GSK-3β with Ki of 0.87 nM. CHIR-98014 is very effective in preventing murine and rat GSK-3. CHIR-98014 exhibits from a 500-fold to >1000-fold selectivity for GSK-3 versus 20 other protein kinases, such as Cdc2, ERK2, Tie-2, and KDR, despite acting as a straightforward competitive inhibitor of ATP binding. CHIR-98014 inhibits Cdc2 with an IC50 of 3.7 M. It is noteworthy that CHIR 98014 only distinguished between GSK-3 and its closest homologs CDC2 and ERK2, even though it exhibits similar potency against the highly homologous and isoforms of GSK-3. A two- to three-fold stimulation of the GS activity ratio above basal is produced when the inhibitor CHIR98014 is applied to insulin receptor-expressing CHO-IR cells or primary rat hepatocytes at increasing concentrations. For rat hepatocytes and CHO-IR, the concentration of CHIR-98014 that causes half-maximal GS stimulation (EC50) is 107 nM.[1]
ln 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.
Enzyme 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. In all cell-free assays, CHIR-98014 or controls are added to 3.5 μL of DMSO, followed by 50 μL of ATP stock to produce a final concentration of 1 μM ATP. Following incubation, triplicate 100-L aliquots are added to Combiplate 8 plates, which have 100-μL/well concentrations of 50 mM ATP and 20 mM EDTA. The wells are rinsed five times with PBS, filled with 200 L of scintillation fluid, sealed, and left for 30 minutes before being counted in a scintillation counter after the first hour. The entire process is carried out 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 a density of 1 × 106 cells/well in 2 mL of medium devoid of fetal bovine serum. After 24 hours, the medium is replaced with 1 mL of serum-free medium containing the 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 g/mL leupeptin (buffer A), and centrifuged for 15 min at 4 °C/14000 g. The GS activity in the absence is used to calculate the activity ratio for GS.
Animal Protocol
Blood is obtained by shallow tail snipping at lidocaine-anesthetized tips. Blood glucose is measured directly or heparinized plasma is collected for measurement of glucose or insulin. Animals are prebled and randomly assigned to vehicle control or GSK-3 inhibitor treatment groups. For glucose tolerance tests (GTTs), animals are fasted throughout the procedure with food removal early in the morning, 3 h before the first prebleed (db/db mice), or the previous night, 16 h before the bleed (ZDF rats). Food is taken away 16 hours prior to the test agent being administered when determining the time course of plasma glucose and insulin changes in fasting ZDF rats. The GS activity ratio is calculated as the GS activity in the presence of 5 mM glucose-6-phosphate divided by the activity in the absence of glucose-6-phosphate.
References

[1]. Diabetes. 2003 Mar;52(3):588-95.

[2]. Br J Pharmacol. 2007 Nov;152(6):959-79.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C20H17CL2N9O2
Molecular Weight
486.3141
Exact Mass
485.08823
Elemental Analysis
C, 49.39; H, 3.52; Cl, 14.58; N, 25.92; O, 6.58
CAS #
252935-94-7
Appearance
Solid powder
SMILES
C1=CC(=C(C=C1Cl)Cl)C2=NC(=NC=C2N3C=CN=C3)NCCNC4=NC(=C(C=C4)[N+](=O)[O-])N
InChi Key
MDZCSIDIPDZWKL-UHFFFAOYSA-N
InChi Code
InChI=1S/C20H17Cl2N9O2/c21-12-1-2-13(14(22)9-12)18-16(30-8-7-24-11-30)10-27-20(29-18)26-6-5-25-17-4-3-15(31(32)33)19(23)28-17/h1-4,7-11H,5-6H2,(H3,23,25,28)(H,26,27,29)
Chemical Name
6-N-[2-[[4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-yl]amino]ethyl]-3-nitropyridine-2,6-diamine
Synonyms
CT-98014; CT 98014; CT98014; CHIR 98014; CHIR-98014; CHIR98014;CHIR98014 HCl; CHIR-98014 hydrochloride
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~8 mg/mL (~16.5 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In Vivo)
10%DMSO+90%corn oil: 1.1mg/mL (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.0563 mL 10.2815 mL 20.5630 mL
5 mM 0.4113 mL 2.0563 mL 4.1126 mL
10 mM 0.2056 mL 1.0282 mL 2.0563 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

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Biological Data
  • CHIR-98014

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

  • CHIR-98014

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

  • CHIR-98014

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

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