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Purity: =98.27%
Laduviglusib (CHIR-99021; CT99021 or CHIR-911) HCl is the hydrochloride salt of CHIR-99021, which is a potent and orally available GSK-3α/β (glycogen synthase kinase 3α/β) inhibitor with IC50 of 10 nM/6.7 nM in cell-free assays; CHIR-99021 was proved to promote self-renewal and maintain pluripotency of both B6 and BALB/c ES cells via stabilizing the downstream effectors like c-Myc and β -catenin. In J1 mESC cells, CHIR-99021, when combined with leukemia inhibitory factor (LIF), was crucial for maintaining colony morphology and self-renewal. It has been demonstrated that CHIR-99021 controls the expression of epigenetic regulatory genes like Dnmt3 as well as several signaling pathways including Wnt/β-catenin, TGF-β, Nodal, and MAPK.
| Targets |
GSK-3β (IC50 = 6.7 nM); GSK-3α (IC50 = 10 nM)
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| ln Vitro |
GSK-3 is more than 500-fold more selective for CHIR-99021 than its nearest homologs, CDC2 and ERK2, as well as other protein kinases. In addition, CHIR-99021 exhibits only modest inhibition of 23 nonkinase enzymes and only weak binding to a panel of 22 pharmacologically significant receptors. With an EC50 of 0.763 μM, CHIR-99021 causes the activation of glycogen synthase (GS) in CHO-IR cells that express the insulin receptor. [1] In addition to mimicking the effects of insulin, CHIR-99021's (3 μM) inhibition of GSK-3 causes an increase in free cytosolic -catenin by 1.9-fold, simulating the canonical Wnt signaling pathway in 3T3-L1 preadipocytes. By preventing the induction of CCAAT/enhancer-binding protein (C/EBP) and peroxisome proliferator-activated receptor γ (PPARγ) during any of the first three days of differentiation, CHIR-99021 treatment prevents preadipocyte differentiation with an IC50 of 0.3 μM. [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 significantly reduces the rate of INS-1E cell death brought on by high glucose and high palmitate in a concentration-dependent manner. It also increases the rate of INS-1E cell proliferation robustly and dose-dependently. At concentrations as low as 1 μM, CHIR-99021 stimulates primary beta cell replication in isolated rat islets, with a 2-3 fold increase in cell replication after treatment with 5 μM of CHIR-99021.[3]
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| ln Vivo |
In a rodent model of type 2 diabetes, oral administration of CHIR-99021 at 30 mg/kg improves glucose metabolism. Three to four hours after oral administration, the maximum plasma glucose reduction—roughly 150 mg/dl—occurs, and plasma insulin levels stay at or below control. In ZDF rats, oral administration of CHIR-99021 at doses of 16 or 48 mg/kg an hour prior to oral glucose challenges significantly improves glucose tolerance, with plasma glucose levels falling by 14% and 33% at the 16 mg/kg and 48 mg/kg doses, respectively. The higher dose of CHIR-99021 also lessens hyperglycemia prior to the oral glucose challenge. [1]
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| 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 27 nM GSK-3α or 29 nM GSK-3β, and 0.5 μM biotin-CREB peptide substrate. In all cell-free assays, different CHIR-99021 concentrations are added to 3.5 μL of DMSO before 50 μL of ATP stock to produce a final concentration of 1 M ATP. Following incubation, triplicate 100-μL aliquots are added to Combiplate 8 plates, which have 100-μL/well concentrations of 50 mM 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.
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| Cell Assay |
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 CHIR-99021 at various concentrations for 1, 3, or 4 days. Cellular DNA is stained with CyQuant dye, which turns fluorescent when bound to DNA, in order to count the number of cells present. Using the FLUOstar Optima reader, fluorescence is measured after 30 minutes of incubation. BrdUrd incorporation controls cell replication. Before the cells are fixed with FixDenat solution and incubated with monoclonal anti-BrdUrd-POD antibodies, BrdUrd labeling solution is added to the medium for the final four hours of the experiment. The light emission is measured in a microplate luminometer using the Analyst HT detection system after substrate solution is added to each well.
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| Animal Protocol |
Female db/db mice or male ZDF rats with type 2 diabetes
~48 mg/kg Orally |
| References |
| Molecular Formula |
C22H19CL3N8
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|---|---|
| Molecular Weight |
501.7989
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| Exact Mass |
500.07982
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| Elemental Analysis |
C, 52.66; H, 3.82; Cl, 21.19; N, 22.33
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| CAS # |
1797989-42-4
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| Related CAS # |
Laduviglusib;252917-06-9;Laduviglusib trihydrochloride;1782235-14-6
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| Appearance |
White to yellow solid powder
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| tPSA |
115Ų
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| SMILES |
CC1=CN=C(N1)C2=CN=C(N=C2C3=C(C=C(C=C3)Cl)Cl)NCCNC4=NC=C(C=C4)C#N.Cl
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| InChi Key |
SCQDMKUZHIGAIB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H18Cl2N8.ClH/c1-13-10-29-21(31-13)17-12-30-22(32-20(17)16-4-3-15(23)8-18(16)24)27-7-6-26-19-5-2-14(9-25)11-28-19;/h2-5,8,10-12H,6-7H2,1H3,(H,26,28)(H,29,31)(H,27,30,32);1H
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| Chemical Name |
6-[2-[[4-(2,4-dichlorophenyl)-5-(5-methyl-1H-imidazol-2-yl)pyrimidin-2-yl]amino]ethylamino]pyridine-3-carbonitrile;hydrochloride
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| Synonyms |
GSK 3IXV; CHIR99021; CHIR 99021; CHIR-911; CHIR911; CHIR 911; CT- 99021; GSK 3 inhibitor XVI; CT-99021; CT- 99021; CHIR-73911; CHIR73911; CHIR 73911
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO: ~100 mg/mL (~199.3 mM)
Water: ~1.5 mg/mL(~3 mM) Ethanol: ~100 mg/mL(~199.3 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (5.98 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 3 mg/mL (5.98 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 3 mg/mL (5.98 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: Formulation 1: ~20 mg/mL (40 mM) in 5% DMSO+30% PEG 300+ddH2O, clear solution Formulation 2: ~5 mg/mL (10 mM) in PBS, clear solution Formulation 3: ≥ 3 mg/mL (6 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + + 45% Saline, clear solution For example, if 1 mL of working solution is to be prepared, you can take 100 μL of 30 mg/mL of DMSO stock solution and add tO + 400 μL of PEG300, mix well (clear solution); Then add 50 μL of Tween 80 to the above solution, mix well (clear solution); Finally, add 450 μL of saline to the above solution, mix well (clear solution). Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Formulation 4: ≥ 3 mg/mL (6 mM) in 10% DMSO + 90% (20% SBE-β-CD in saline), clear solution For example, if 1 mL of working solution is to be prepared, you can take 100 μL of 30 mg/mL of DMSO stock solution and add to 900 μL of 20% SBE-β-CD in saline, mix well (clear solution). Preparation of 20% SBE-β-CD in Saline (（4°C，1 week）): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Formulation 5: ≥ 3 mg/mL (6 mM) in 10% DMSO + 90% Corn oil, clear solution For example, if 1 mL of working solution is to be prepared, you can take 100 μL of 30 mg/mL of DMSO stock solution and add to 900 μL of corn oil, mix well (clear solution). Solubility in Formulation 5: 5 mg/mL (9.96 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9928 mL | 9.9641 mL | 19.9283 mL | |
| 5 mM | 0.3986 mL | 1.9928 mL | 3.9857 mL | |
| 10 mM | 0.1993 mL | 0.9964 mL | 1.9928 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.
Calculation results
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.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03616223 | Completed | Drug: FX-322 Drug: Placebo |
Sensorineural Hearing Loss |
Frequency Therapeutics | July 3, 2018 | Phase 1 Phase 2 |
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