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CHIR-98014

CHIR-98014

Item no.	S2745-5
Manufacturer	Selleckchem
CASRN	252935-94-7
Amount	5 mg
Quantity options	100 mg 1 g 10 g 10 mM/1 mL 25 mg 5 mg 5 g
Category	Neuroscience Metabolism Diabetes Cholesterol & Lipid Metabolism Regulation of Appetite Neural Signaling Inhibitors & Compound Libraries Small Molecules
Type	Inhibitors
Specific against	other
Smiles	C1=CC(=C(C=C1Cl)Cl)C2=NC(=NC=C2N3C=CN=C3)NCCNC4=NC(=C(C=C4)[N+](=O)[O-])N
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	CT98014
Similar products	CHIR-98014
Available
Storage Conditions	2 years -80 in solvent
Molecular Weight	486, 31
Administration	Subcutaneously
Animal Models	db/db mice with 8-9 weeks
Cell lines	CHO-IR cells
Concentrations	0.01-10 uM
Dosages	30 mg/kg
Formulation	15% Captisol/citrate vehicle
IC50	0.65 nM, 0.65 nM, 0.65 nM, 0.65 nM, 0.65 nM, 0.65 nM
In vitro	CHIR-98014 inhibits human GSK-3beta 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 uM. However, CHIR 98014 reveals similar ptoency against the highly homologous and beta 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. [1]
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. [1] Additionally, CHIR-98014 decreases the phosphorylation (Ser396) of tau protein in the cortex and hippocampus of postnatal rats. [2]
Incubation Time	30 min
Kinase Assay	Kinase assays, Polypropylene 96-well plates are lled with 300 uL/well buffer (50 mM tris HCl, 10 mM MgCl2, 1 mM EGTA, 1 mM dithiothreitol, 25 mM beta-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 uL of DMSO, followed by 50 uL of ATP stock to yield a nal concentration of 1 uM ATP in all cell-free assays. After incubation, triplicate 100-uL aliquots are transferred to Combiplate eight plates containing 100 uL/well 50 uM ATP and 20 mM EDTA. After 1 hour, the wells are rinsed ve times with PBS, lled with 200 uL of scintillation uid, sealed, left 30 min, and counted in a scintillation counter. All steps are performed at room temperature.
Method	CHO-IR cells expressing human insulin receptor are grown to 80% con uence in Hamms 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 ( nal 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 uoride, and 25 g/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.
Solubility (25C)	DMSO 4 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL
Information	CHIR-98014 (CT98014) is a potent GSK-3α/β inhibitor with IC50 of 0.65 nM/0.58 nM in cell-free assays, with the ability to distinguish GSK-3 from its closest homologs Cdc2 and ERK2.
Chemical Name	N2-(2-(4-(2, 4-dichlorophenyl)-5-(1H-imidazol-1-yl)pyrimidin-2-ylamino)ethyl)-5-nitropyridine-2, 6-diamine

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