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| 10mg |
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| 25mg |
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| 250mg |
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Purity: ≥98%
CCT251545 is a novel, potent, selective and orally bioavailable small-molecule inhibitor of WNT signaling with an IC50 of 5 nM in 7dF3 cells. It was discovered through cell-based screening and can be used as a selective chemical probe for the human Mediator complex-associated protein kinases CDK8 and CDK19 with >100-fold selectivity over 291 other kinases. In contrast to type II inhibitors of CDK8 and CDK19, CCT251545 displays potent cell-based activity. CCT251545 alters WNT pathway-regulated gene expression and other on-target effects of modulating CDK8 and CDK19, including expression of genes regulated by STAT1. CCT251545 and close analogs alter WNT pathway-regulated gene expression and other on-target effects of modulating CDK8 and CDK19, including expression of genes regulated by STAT1. Consistent with this, it was found that phosphorylation of STAT1(SER727) is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally, the in vivo activity of CCT251545 in WNT-dependent tumors was evaluated.
| ln Vitro |
CCT251545 substantially suppresses WNT pathway activity in COLO205-F1756 clone 4, an APC mutant human colorectal cancer cell line that is designed to express a luciferase-based WNT reporter construct, with an IC50 of 0.035 μM [1]. Tankyrase is weakly inhibited by CCT251545 (TNKS1 IC50 > 10 μM, TNKS2 IC50 = 15.0) [1]. With more than 100-fold selectivity over 291 other kinases, CCT251545 is an efficient and specific chemical probe for identifying human mediator complex-associated protein kinases CDK8 and CDK19 [2]. In addition to modulating additional on-target effects of CDK8 and CDK19, such as gene expression regulated by STAT1, CCT251545 modifies the expression of genes regulated by the WNT pathway [2]. Additionally, CCT251545, with an IC50 of 9 nM, lowers the levels of phospho-STAT1SER727 in SW620 cells [2]. Cell-based action is strong in CCT251545 [2].
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| ln Vivo |
Tumor growth is inhibited in NCr athymic mice bearing established SW620 human colorectal cancer xenografts by CCT251545 (70 mg/kg; oral; twice daily) [2].
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| Animal Protocol |
Animal/Disease Models: 6-8 week female NCr athymic mice with established SW620 xenografts [2]
Doses: 70mg/kg Route of Administration: Oral; Route of Administration: twice (two times) daily; Days 0-7 And the results on days 10-14: tumor growth was inhibited, and the final tumor weight was diminished by 70% relative to the control. |
| References |
[1]. Mallinger A, et al. Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen. J Med Chem. 2015 Feb 26;58(4):1717-35.
[2]. Dale T, et al. A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. Nat Chem Biol. 2015 Dec;11(12):973-980. |
| Molecular Formula |
C23H24CLN5O
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|---|---|
| Molecular Weight |
421.9226
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| CAS # |
1661839-45-7
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| SMILES |
O=C1NCCC12CCN(C3=C(Cl)C=NC=C3C4=CC=C(C5=CN(C)N=C5)C=C4)CC2
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| InChi Key |
LBFYQISQYCGDDW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H24ClN5O/c1-28-15-18(12-27-28)16-2-4-17(5-3-16)19-13-25-14-20(24)21(19)29-10-7-23(8-11-29)6-9-26-22(23)30/h2-5,12-15H,6-11H2,1H3,(H,26,30)
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| Chemical Name |
8-(3-chloro-5-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyridin-4-yl)-2,8-diazaspiro[4.5]decan-1-one
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| Synonyms |
CCT251545; CCT 251545; CCT-251545;
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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 : ≥ 50 mg/mL (~118.51 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (3.96 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 16.7 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: ≥ 1.67 mg/mL (3.96 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 16.7 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: ≥ 1.67 mg/mL (3.96 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 | 2.3701 mL | 11.8506 mL | 23.7012 mL | |
| 5 mM | 0.4740 mL | 2.3701 mL | 4.7402 mL | |
| 10 mM | 0.2370 mL | 1.1851 mL | 2.3701 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.
 Identification of the molecular targets of CCT251545.
Altered CDK8/19 expression affects WNT-regulated transcription.Nat Chem Biol.2015 Dec;11(12):973-980. |
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 X-ray crystal structural analysis of compound 1 bound to CDK8/cyclin C.
Characterisation of the interaction between CDK8/19 and the 3,4,5-trisubstituted pyridine series.Nat Chem Biol.2015 Dec;11(12):973-980. |
 Gene transcript profiling following inhibition of WNT signalling resulting from loss of β-Catenin or following treatment with 3,4,5-trisubstituted pyridines.
Biomarker modulation and therapeutic effects of compound 1 in human cancer cell lines andin vivoanimal models.Nat Chem Biol.2015 Dec;11(12):973-980. |
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