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| Targets |
GSK-3β inhibitor 2 targets glycogen synthase kinase-3β (GSK-3β), a ubiquitously expressed serine/threonine kinase that plays critical roles in glycogen metabolism, cell cycle regulation, Wnt signaling, and neuronal function. GSK-3β is involved in the phosphorylation and regulation of numerous substrates, including glycogen synthase, β-catenin, and tau protein. Dysregulation of GSK-3β has been implicated in Alzheimer's disease, diabetes, cancer, and mood disorders. The compound inhibits GSK-3β with an IC₅₀ of 1.1 nM, indicating exceptionally high potency. Its ability to cross the blood-brain barrier makes it particularly relevant for central nervous system applications, such as Alzheimer's disease research.
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| ln Vitro |
GSK-3β inhibitor 2 (compound 3)'s pyridine carboxamide establishes a hydrogen bond with the hinge V135 skeleton amide, while the thiazolyl primary amide's carbonyl oxygen forms a crucial hydrogen bond with K85. The methyl group's electron density quality in the methoxy moiety of GSK-3β inhibitor 2 prevents it from having a definite position in the model; however, single crystal X-ray diffraction, a small molecule crystal structure approach, validated this position. It was discovered that GSK-3β inhibitor 2 contains an intramolecular hydrogen bond between amide NH and methoxy-O- [1].
In vitro, GSK-3β inhibitor 2 demonstrates potent and selective inhibition of GSK-3β with an IC₅₀ of 1.1 nM. The compound is orally active and can cross the blood-brain barrier. It is a synthetic small-molecule inhibitor that targets the ATP-binding site of GSK-3β. The compound's high potency and selectivity make it a valuable tool for studying GSK-3β biology and developing therapies for Alzheimer's disease and other GSK-3β-related disorders. In vitro studies may assess the compound's effects on GSK-3β substrates, including glycogen synthase phosphorylation, β-catenin stability, and tau phosphorylation. Cytotoxicity and selectivity profiling against other kinases are typically performed to confirm specificity. |
| ln Vivo |
Mice LaFerla 3xTg-C57BL6 are employed as an in vivo model of Alzheimer's disease because they exhibit elevations in hyperphosphorylated Tau (pTau). Oral administration of GSK-3β inhibitor 2 (Compound 3) as a nanosuspension at 30 mg/kg resulted in a significant decrease in pTau396 in LaFerla 3xTg-C57BL6 male mice. As assessed at a single time point, GSK-3β inhibitor 2 only modestly exposed the brain (B/P = 0.26) [1].
In vivo, GSK-3β inhibitor 2 has potential applications in Alzheimer's disease research. The compound's ability to cross the blood-brain barrier and its oral activity make it a promising candidate for in vivo studies. In animal models of Alzheimer's disease, GSK-3β inhibitors have been shown to reduce tau phosphorylation, amyloid-β pathology, and cognitive deficits. The compound may also have applications in diabetes, cancer, and mood disorders, where GSK-3β dysregulation plays a role. However, detailed in vivo efficacy, pharmacokinetic, and toxicological data for GSK-3β inhibitor 2 require further investigation from primary research publications. |
| Enzyme Assay |
In vitro enzyme/receptor binding (non-cellular) assays for GSK-3β inhibitor 2 involve measuring inhibition of GSK-3β kinase activity using recombinant enzyme and a peptide substrate. The assay typically uses a radioactive (³³P-ATP) or fluorescence-based method to detect phosphorylation of the substrate. The enzyme is incubated with varying concentrations of the compound, ATP, and substrate in kinase assay buffer (typically 50 mM HEPES, pH 7.5, with 10 mM MgCl₂ and 1 mM DTT). The reaction is terminated, and the phosphorylated substrate is quantified. IC₅₀ values are calculated from concentration-response curves. The IC₅₀ of 1.1 nM for GSK-3β inhibition is determined using this assay format.
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| Cell Assay |
In vitro cellular experiments with GSK-3β inhibitor 2 are performed using various cell lines to assess its effects on GSK-3β signaling. Cells such as SH-SY5Y (neuroblastoma), HEK293, or primary neurons are cultured in appropriate media and treated with varying concentrations of the compound for 24-72 hours. GSK-3β activity is assessed by measuring the phosphorylation of its substrates, including glycogen synthase (Ser641) and β-catenin (Ser33/37/Thr41), using Western blot analysis with phospho-specific antibodies. Tau phosphorylation may also be assessed in neuronal cell lines. Cell viability and proliferation are assessed using MTT or CellTiter-Glo assays. The compound's ability to cross the blood-brain barrier is relevant for CNS applications.
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| Animal Protocol |
In vivo animal studies with GSK-3β inhibitor 2 have not been extensively reported. For Alzheimer's disease research, standard in vivo models include transgenic mouse models such as APP/PS1 or 3xTg-AD mice, as well as tauopathy models. Mice are treated with GSK-3β inhibitor 2 via oral administration at various doses and schedules. Efficacy is assessed by measuring tau phosphorylation, amyloid-β pathology, synaptic markers, and cognitive function using behavioral tests (Morris water maze, novel object recognition). Pharmacodynamic markers such as GSK-3β substrate phosphorylation in brain tissues may be measured to confirm target engagement. The compound's oral activity and blood-brain barrier penetration are key advantages for in vivo applications.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of GSK-3β inhibitor 2 are not extensively characterized. The compound has molecular formula C₁₄H₁₄N₄O₃S and molecular weight 318.35. It is a small molecule (molecular weight 318.35) that is orally active and can cross the blood-brain barrier. These properties suggest favorable absorption, distribution, and brain penetration. The compound is soluble in DMSO at 5 mg/mL. Storage: powder at -20°C for 3 years or 4°C for 2 years. Detailed pharmacokinetic parameters including half-life, clearance, bioavailability, and brain-to-plasma ratio require further investigation from primary research publications.
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| Toxicity/Toxicokinetics |
Toxicological information for GSK-3β inhibitor 2 is not extensively detailed in the available literature. As a research compound with kinase inhibitory activity, it should be handled with appropriate safety precautions. Standard safety guidelines for handling potent pharmaceutical compounds apply, including use of personal protective equipment (gloves, safety goggles, lab coat), working in a well-ventilated area, and proper chemical waste disposal. The compound is intended for research use only and is not approved for human therapeutic use. Cytotoxicity studies in cell-based assays help establish the therapeutic window and selectivity index of the compound.
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| References | |
| Additional Infomation |
GSK-3β inhibitor 2 (CAS 1702428-31-6) is a potent, selective, and orally active glycogen synthase kinase-3β (GSK-3β) inhibitor with an IC₅₀ of 1.1 nM. The compound has molecular formula C₁₄H₁₄N₄O₃S and molecular weight 318.35. GSK-3β inhibitor 2 can cross the blood-brain barrier and has potential applications in Alzheimer's disease research. The compound is also known as Compound 3. It is a synthetic small-molecule inhibitor that targets GSK-3β, a serine/threonine kinase involved in multiple cellular processes including glycogen metabolism, cell cycle regulation, and neuronal function. Purity is typically ≥98%. Storage: powder at -20°C for 3 years or 4°C for 2 years.
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| Molecular Formula |
C14H14N4O3S
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| Molecular Weight |
318.350961208344
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| Exact Mass |
318.078
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| CAS # |
1702428-31-6
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| PubChem CID |
73333976
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
1
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
22
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| Complexity |
446
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S1C(C(N)=O)=C(N=C1C1C=CN=C(C=1)NC(C1CC1)=O)OC
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| InChi Key |
CYADPSMQNARVII-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C14H14N4O3S/c1-21-13-10(11(15)19)22-14(18-13)8-4-5-16-9(6-8)17-12(20)7-2-3-7/h4-7H,2-3H2,1H3,(H2,15,19)(H,16,17,20)
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| Chemical Name |
2-[2-(cyclopropanecarbonylamino)pyridin-4-yl]-4-methoxy-1,3-thiazole-5-carboxamide
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| Synonyms |
GSK3β inhibitor 2; GSK 3β inhibitor 2
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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 : ~5 mg/mL (~15.71 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1412 mL | 15.7060 mL | 31.4120 mL | |
| 5 mM | 0.6282 mL | 3.1412 mL | 6.2824 mL | |
| 10 mM | 0.3141 mL | 1.5706 mL | 3.1412 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.
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