| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
CDK8 and CDK19. CCT251921 is a potent, selective, and orally bioavailable small-molecule inhibitor of CDK8 and CDK19. These kinases are key components of the Mediator complex's kinase module, which regulates gene transcription. CCT251921 inhibits CDK8 with an IC50 of 2.3 nM and CDK19 with an IC50 of 2.6 nM. By inhibiting these kinases, it modulates the Wnt/β-catenin signaling pathway and reduces phosphorylation of STAT1 at serine 727 (pSTAT1(Ser727)), which serves as a robust pharmacodynamic biomarker.
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| ln Vitro |
Tested on a panel of 279 kinases, 55 receptors, ion channels, and enzymes at 1 μM, CCT-251921 has an acceptable water solubility and minimal activity; weak inhibition of CYP was seen. In human cancer cell lines with constitutively activated WNT pathway signaling, such as LS174T (β-catenin mutant), SW480, Colo205 (APC mutant), or PA-1 human teratocarcinoma WNT ligand-dependent cells, CCT-251921 exhibits potent inhibition of reporter gene-based readouts measuring basal WNT pathway activity [1].
In vitro, CCT251921 is a potent inhibitor of CDK8 (IC50 = 2.3 nM) and CDK19 (IC50 = 2.6 nM). It exhibits limited activity across a panel of 55 receptors, ion channels, and enzymes at 1 μM, as well as a panel of 279 kinases. It effectively inhibits basal WNT pathway activity in human cancer cell lines with constitutive activation of WNT signaling, including LS174T, SW480, Colo205, and PA-1 cells. It also shows weak inhibition of CYPs. |
| ln Vivo |
For the purpose of advancing preclinical efficacy and safety investigations as well as facilitating additional assessment of CDK8/19 pharmacology, CCT-251921 shows enhanced oral pharmacokinetics and pharmacological characteristics. CCT-251921 therapy decreased mouse tumor weight (54.2%) at day 15 in an APC mutant SW620 human colorectal cancer xenograft model. After the last dosage, STAT1SER727 phosphorylation inhibition lasts for longer than six hours [1].
CCT251921 has demonstrated significant in vivo anti-tumor activity. In an APC-mutant SW620 human colorectal carcinoma xenograft model, treatment with CCT251921 reduced tumor weight in mice by 54.2% on day 15. It maintains inhibition of STAT1SER727 phosphorylation for over 6 hours post-dose. In an experimental autoimmune encephalomyelitis (EAE) model, treatment with CCT251921 significantly increased Treg population and ameliorated autoimmune symptoms. |
| Enzyme Assay |
The activity of CCT251921 as a CDK8/19 inhibitor is assessed using in vitro biochemical kinase assays. A LanthaScreen binding assay is commonly used to determine the IC50 values for CDK8 (2.3 nM) and CDK19 (2.6 nM). Selectivity profiling against a broad panel of kinases, receptors, ion channels, and enzymes is performed to confirm its specificity.
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| Cell Assay |
Cellular assays for CCT251921 involve treating cancer cell lines with the compound and measuring its effects on cell proliferation, viability, and signaling pathways. The compound's ability to inhibit WNT pathway activity is assessed in cell lines with constitutive WNT signaling, such as LS174T, SW480, and Colo205. Target engagement is confirmed by measuring the reduction in pSTAT1(Ser727) levels, a robust pharmacodynamic biomarker.
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| Animal Protocol |
In vivo animal model protocols for CCT251921 involve its oral administration to tumor-bearing mice. In a SW620 human colorectal carcinoma xenograft model, the compound was administered to evaluate its anti-tumor efficacy, resulting in a 54.2% reduction in tumor weight on day 15. In an EAE model, it was used to study its effects on Treg cell differentiation and autoimmune symptoms.
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| ADME/Pharmacokinetics |
CCT251921 is an orally bioavailable compound. In mice, it has a plasma half-life of 0.78 h, a systemic clearance of 0.61 L/h/Kg, a bioavailability of 30%, and a volume of distribution of 0.63 L/Kg. In rats, the half-life is 1.10 h, clearance is 1.49 L/h/Kg, bioavailability is 57%, and volume of distribution is 2.0 L/Kg. In dogs, the half-life is 0.99 h, clearance is 1.07 L/h/Kg, and bioavailability is 68%.
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| Toxicity/Toxicokinetics |
Specific toxicological data for CCT251921 is not extensively detailed in the available literature. As a research compound, it is intended for research use only and not for human consumption. Standard safety assessments would be required for clinical development. The compound is typically stored as a powder at -20°C for long-term stability.
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| References | |
| Additional Infomation |
CCT251921 (CAS# 1607837-31-9) is a research compound used to study CDK8 and CDK19 function. It is a potent, selective, and orally bioavailable inhibitor of these kinases, with IC50 values of 2.3 nM and 2.6 nM, respectively. It is a first-in-class chemical probe for the Mediator complex-associated kinases. It has demonstrated significant anti-tumor activity in preclinical models of colorectal cancer. It is not approved for clinical use and is supplied as a research chemical.
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| Molecular Formula |
C21H23CLN6O
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|---|---|
| Molecular Weight |
410.8999
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| Exact Mass |
410.162
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| CAS # |
1607837-31-9
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| PubChem CID |
74222277
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
696.4±55.0 °C at 760 mmHg
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| Flash Point |
375.0±31.5 °C
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| Vapour Pressure |
0.0±2.2 mmHg at 25°C
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| Index of Refraction |
1.757
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| LogP |
2.78
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
29
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| Complexity |
626
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
VPJXPDLMACOGIZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H23ClN6O/c1-27-16-3-2-13(10-14(16)11-26-27)15-12-25-19(23)17(22)18(15)28-8-5-21(6-9-28)4-7-24-20(21)29/h2-3,10-12H,4-9H2,1H3,(H2,23,25)(H,24,29)
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| Chemical Name |
8-(2-amino-3-chloro-5-(1-methyl-1H-indazol-5-yl)pyridin-4-yl)-2,8-diazaspiro[4.5]decan-1-one
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| Synonyms |
CCT251921 CCT-251921 CCT 251921
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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 : ~25 mg/mL (~60.84 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.08 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 (6.08 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 (6.08 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 | 2.4337 mL | 12.1684 mL | 24.3368 mL | |
| 5 mM | 0.4867 mL | 2.4337 mL | 4.8674 mL | |
| 10 mM | 0.2434 mL | 1.2168 mL | 2.4337 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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