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Chemical Information
| Catalog Num | A10199 |
|---|---|
| Actions | Inhibitor |
| M. Wt | 465.3 |
| Formula | C22H18Cl2N8 |
| Solubility | DMSO |
| Purity | >98% |
| Storage | at -20°C 3 years Powder |
| CAS No. | 252917-06-9 |
| Synonyms | GSK-3 Inhibitor XVI, CT 99021, CHIR99021 |
| SMILES | CC1=CN=C(N1)C2=CN=C(N=C2C3=C(C=C(C=C3)Cl)Cl)NCCNC4=NC=C(C=C4)C#N |
| Chemical Name | 6-[2-[4-(2,4-Dichlorophenyl)-5-(4-methyl-1H-imidazol-2-yl)pyrimidin-2-ylamino]ethylamino]pyridine-3-carbonitrile |
Description |
CHIR99021 is an aminopyrimidine derivative that inhibits GSK3α and GSK3β with IC50 values of 10 and 6.7 nM, respectively. | ||||||||||
Targets |
|
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| Solubility (25°C)* | In vitro | DMSO | 78 mg/mL warmed (167.61 mM) |
|---|---|---|---|
| Water | <1 mg/mL (<1 mM) | ||
| Ethanol | <1 mg/mL (<1 mM) | ||
|
* <1 mg/ml means slightly soluble or insoluble. * Please note that Adooq tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. |
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| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 0.1 mM | 21.49 mL | 107.46 mL | 214.92mL |
| 0.5 mM | 4.3 mL | 21.49 mL | 42.98 mL |
| 1 mM | 2.15 mL | 10.75 mL | 21.49 mL |
| 5 mM | 0.43 mL | 2.15 mL | 4.3 mL |
*The above data is based on the productmolecular weight 465.3 . Batch specific molecular weights may vary from batch to batch due to solvent of hydration, which will affect the solvent volumes required to prepare stock solutions.
Biological Activity
| Description | CHIR-99021 HCl (CT99021) is hydrochloride of CHIR-99021, which is a GSK-3α/β inhibitor with IC50 of 10 nM/6.7 nM; ability to distinguish between GSK-3 and its closest homologs Cdc2 and ERK2. | |||||
|---|---|---|---|---|---|---|
| Targets |
GSK-3α |
GSK-3β |
||||
| IC50 |
10 nM |
6.7 nM [1] |
||||
| In vitro | CHIR-99021 shows greater than 500-fold selectivity for GSK-3 versus its closest homologs CDC2 and ERK2, as well as other protein kinases. Furthermore, CHIR-99021 shows only weak binding to a panel of 22 pharmacologically relevant receptors and little inhibitory activity against a panel of 23 nonkinase enzymes. CHIR-99021 induces the activation of glycogen synthase (GS) in insulin receptor-expressing CHO-IR cells with EC50 of 0.763 μM. [1] In addition to simulating the actions of insulin, inhibition of GSK-3 by CHIR-99021 (3 μM) increases free cytosolic β-catenin by 1.9-fold, mimicking the canonical Wnt signaling pathway in 3T3-L1 preadipocytes. During any of the first 3 days of differentiation, CHIR-99021 treatment inhibits the preadipocyte differentiation with IC50 of 0.3 μM by blocking induction of CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ). [2] Unlike lithium chloride and AR-A014418, CHIR-99021 treatment does not reduce the viability of INS-1E cells even at high concentrations. Instead, CHIR-99021 robustly increases the rate of proliferation of INS-1E cells in a dose-dependent manner, and significantly inhibits INS-E cell death induced by high glucose and high palmitate in a concentration-dependent manner. CHIR-99021 promotes primary beta cell replication in isolated rat islets at concentrations as low as 1 μM, with 2-3 fold increase of cell replication at 5 μM of CHIR-99021 treatment. [3] | |||||
| In vivo | Oral administration of CHIR-99021 at 30 mg/kg enhances glucose metabolism in a rodent model of type 2 diabetes, with a maximal plasma glucose reduction of nearly 150 mg/dl 3-4 hours after administration, while plasma insulin remains at or below control levels. Oral administration of CHIR-99021 at 16 or 48 mg/kg 1 hour before oral glucose challenges in ZDF rats significantly improves glucose tolerance with 14% and 33% reduction in plasma glucose at 16 mg/kg and 48 mg/kg, respectively, and the higher dose of CHIR-99021 also reduces hyperglycemia before the oral glucose challenge. [1] Administration of CHIR-99021 significantly augments hematopoietic repopulation in recipient mice transplanted with mouse or human hematopoietic stem cells (HSCs), suggesting that GSK-3 is a specific modulator of HSC activity. [4] | |||||
| Features | ||||||
Protocol(Only for Reference)
Kinase Assay:
| Cell-free kinase assays | 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 27 nM GSK-3α or 29 nM GSK-3β, and 0.5 μM biotin-CREB peptide substrate. Various concentrations of CHIR-99021 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 minutes, and counted in a scintillation counter. All steps are performed at room temperature. |
|---|
Cell Assay:
| Cell lines | INS-1E |
|---|---|
| Concentrations | Dissolved in DMSO, final concentrations ~ 20 μM |
| Incubation Time | 1, or 4 days |
| Method |
Cells are maintained for 24 hours in starvation medium (culture medium with only 5 mM glucose, 1% fetal calf serum). Then cells are exposed to various concentrations of CHIR-99021 for 1, or 4 days. Cell number is measured by staining of cellular DNA with CyQuant dye, which becomes fluorescent when bound to DNA. Fluorescence is measured after 30 minutes of incubation using the FLUOstar Optima reader. Cell replication is determined by BrdUrd incorporation. BrdUrd labeling solution is added to the medium for the last 4 hours before the cells are fixed using FixDenat solution and incubated with monoclonal anti-BrdUrd-POD antibodies. After substrate solution is added to each well, the light emission is measured in a microplate luminometer using the Analyst HT detection system. |
Animal Study:
| Animal Models | Female db/db mice or male ZDF rats with type 2 diabetes |
|---|---|
| Formulation | Formulated as solutions in 20 mM citrate-buffered 15% Captisol or as fine suspensions in 0.5% carboxymethylcellulose. |
| Dosages | ~48 mg/kg |
| Administration | Orally |
Reference
1.Ring DB, et al. Diabetes, 2003, 52(3), 588-595.
2.Bennett CN, et al. J Biol Chem, 2002, 277(34), 30998-31004.
3.Mussmann R, et al. J Biol Chem, 2007, 282(16), 12030-12037.
4.Trowbridge JJ, et al. Nat Med, 2006, 12(1), 89-98.
5.Nichols J, et al. Development, 2009, 136(19), 3215-3222.
6.Kawamata M, et al. Proc Natl Acad Sci U S A, 2010, 107(32), 14223-14228.
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