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| 1mg |
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| 10mg |
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| Targets |
The compound targets three important kinases involved in cell cycle regulation and neuronal function: CDK2 (cyclin-dependent kinase 2), a key regulator of the G1/S cell cycle transition; CDK5 (cyclin-dependent kinase 5), which plays important roles in neuronal development, synaptic plasticity, and neurodegeneration; and GSK-3 (glycogen synthase kinase-3), which is involved in glycogen metabolism, Wnt signaling, and tau hyperphosphorylation in Alzheimer's disease.
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| ln Vitro |
With an IC50 of less than around 50 μM, GSK-3/CDK5/CDK2-IN-1 suppresses the phosphorylation of the cdk5 peptide substrate [1].
GSK-3/CDK5/CDK2-IN-1 inhibits the phosphorylation of a CDK5 peptide substrate with an IC50 of less than approximately 50 microM. The compound also inhibits CDK2 and GSK-3 with similar potency. While not a highly potent inhibitor individually (IC50 ~50 microM is considered modest), its multi-kinase activity makes it a useful tool for studying the overlapping or cooperative roles of these three kinases in various cellular processes, including cell cycle progression, neuronal survival, and apoptosis. |
| ln Vivo |
Specific in vivo data for GSK-3/CDK5/CDK2-IN-1 are not detailed in the literature. As a multi-kinase inhibitor that targets CDK5, CDK2, and GSK-3, the compound would be expected to show efficacy in animal models of cancer (e.g., those driven by CDK2 hyperactivity) and neurodegenerative diseases (e.g., Alzheimer's disease, where GSK-3 and CDK5 contribute to tau hyperphosphorylation and neurofibrillary tangle formation). A typical protocol would involve intraperitoneal administration in mouse models.
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| Enzyme Assay |
The biochemical kinase assay is performed using a standard kinase inhibition protocol. Purified recombinant human CDK5/p25 complex (or CDK2/cyclin A/E, or GSK-3beta) is incubated with a specific peptide substrate (e.g., histone H1 peptide for CDK5, glycogen synthase peptide for GSK-3), ATP (at Km concentration), and varying concentrations of the compound in reaction buffer (20 mM MOPS, pH 7.2, 25 mM beta-glycerophosphate, 5 mM EGTA, 1 mM sodium orthovanadate, 1 mM DTT). After incubation at 30degC for 30-60 minutes, the reaction is stopped, and the amount of phosphorylated peptide is measured using a luminescent ADP-Glo assay or a radiometric method with 32P-ATP. The IC50 is calculated from the dose-response curve.
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| Cell Assay |
A cellular assay can be performed in cancer cell lines (e.g., HeLa, MCF-7) or neuronal cell lines (e.g., SH-SY5Y). Cells are seeded in 96-well plates and treated with varying concentrations of GSK-3/CDK5/CDK2-IN-1 (1-100 microM) for 24-72 hours. Cell viability is measured using MTT or CellTiter-Glo assays to determine anti-proliferative activity. For pathway analysis, cells are treated for 2-24 hours, and cell lysates are analyzed by Western blot using phospho-specific antibodies against known substrates: for CDK5, anti-phospho-Tau (Ser202/Thr205, AT8 antibody); for CDK2, anti-phospho-Rb (Ser780 or Ser807/811); for GSK-3, anti-phospho-GSK-3alpha/beta (Ser21/9) or anti-phospho-beta-catenin (Ser33/37/Thr41).
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| Animal Protocol |
In vivo animal experimental procedures are not detailed. A typical study in an Alzheimer's disease model would use the 3xTg-AD mouse or the P301S tau transgenic mouse. Mice (6-8 months old) are administered GSK-3/CDK5/CDK2-IN-1 via intraperitoneal injection at doses of 10-50 mg/kg daily for 4-8 weeks. Cognitive function is assessed using the Morris water maze or novel object recognition test. Upon study termination, brains are harvested for analysis of tau phosphorylation (using PHF-1 and AT8 antibodies) by Western blot and immunohistochemistry. For cancer studies, a mouse xenograft model with tumor cells is used.
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| ADME/Pharmacokinetics |
Specific PK parameters for this compound are not detailed. As a small-molecule imidazole analog (MW 362.4), the compound would likely be administered intraperitoneally in animal studies. Key PK parameters such as bioavailability, half-life, and brain penetration (for neurodegenerative disease applications) would require empirical determination. The ability to cross the blood-brain barrier is critical for studies in Alzheimer's disease models.
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| Toxicity/Toxicokinetics |
Specific toxicological data for this compound are not detailed. As a multi-kinase inhibitor, off-target effects are a potential concern. However, the compound's IC50 of approximately 50 microM is modest, meaning higher concentrations would be required to achieve efficacy, potentially increasing the risk of off-target toxicity. Standard toxicological endpoints (body weight, general health, organ histopathology) would be assessed in animal studies. At lower doses, off-target effects may be minimal.
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| References | |
| Additional Infomation |
GSK-3/CDK5/CDK2-IN-1 is a research-grade chemical tool for studying the combined roles of CDK2, CDK5, and GSK-3 in cancer and neurodegenerative diseases. These three kinases are interconnected in regulating cell cycle progression, neuronal survival, and tau pathology. The compound is particularly valuable for investigating the crosstalk between these pathways and for developing multi-targeted therapeutic strategies, as single-target inhibitors have shown limited efficacy in complex diseases. As of the latest updates, the compound has not been approved for clinical use.
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| Molecular Formula |
C21H22N4O2
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|---|---|
| Molecular Weight |
362.42498
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| Exact Mass |
362.174
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| CAS # |
395074-72-3
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| PubChem CID |
10155554
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| Appearance |
White to off-white solid powder
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| LogP |
2.2
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
27
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| Complexity |
548
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(NC1CC(N2C=C(NC(=O)CC3C=CC4C(=CC=CC=4)C=3)N=C2)C1)(=O)C
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| InChi Key |
XJRCZTVFSOVAQW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H22N4O2/c1-14(26)23-18-10-19(11-18)25-12-20(22-13-25)24-21(27)9-15-6-7-16-4-2-3-5-17(16)8-15/h2-8,12-13,18-19H,9-11H2,1H3,(H,23,26)(H,24,27)
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| Chemical Name |
N-[1-(3-acetamidocyclobutyl)imidazol-4-yl]-2-naphthalen-2-ylacetamide
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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 (~275.92 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.90 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 25.0 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: ≥ 2.5 mg/mL (6.90 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 25.0 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: ≥ 2.5 mg/mL (6.90 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7592 mL | 13.7958 mL | 27.5915 mL | |
| 5 mM | 0.5518 mL | 2.7592 mL | 5.5183 mL | |
| 10 mM | 0.2759 mL | 1.3796 mL | 2.7592 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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