CCT251545

CCT251545 is a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. CCT251545 is a potent and 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.

Product information

CAS Number: 1661839-45-7

Molecular Weight: 421.92

Formula: C23H24ClN5O

Synonym:

CCT 251545

CCT-251545

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

Smiles: CN1C=C(C=N1)C1C=CC(=CC=1)C1=CN=CC(Cl)=C1N1CCC2(CCNC2=O)CC1

InChiKey: LBFYQISQYCGDDW-UHFFFAOYSA-N

InChi: 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)

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Soluble in DMSO, not in water

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

CCT251545 potently inhibits WNT pathway activity in COLO205-F1756 clone 4 (an APC -mutant human colorectal cancer cell line engineered to express a modified luciferase-based WNT reporter construct) with an IC50 of 0.035 μM. CCT251545 has weak inhibition of tankyrase enzymes (TNKS1 IC50 > 10 μM, TNKS2 IC50 = 15.0). CCT251545 is a potent and selective chemical probe for the human mediator complex-associated protein kinases CDK8 and CDK19 with >100-fold selectivity over 291 other kinases. 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 also reduces phospho-STAT1SER727 levels in SW620 cells with an IC50 of 9 nM. CCT251545 displays potent cell-based activity.

In Vivo:

CCT251545 (70mg/kg; p.o.; twice daily) causes an inhibition of tumor growth in NCr athymic mice bearing established SW620 human colorectal cancer xenografts.

References:

1. Dale T, Clarke PA, Esdar C, Waalboer D, Adeniji-Popoola O, Ortiz-Ruiz MJ,Mallinger A, Samant RS, Czodrowski P, Musil D, Schwarz D, Schneider K, Stubbs M, Ewan K, Fraser E, TePoele R, Court W, Box G, Valenti M, de Haven Brandon A, Gowan S, Rohdich F, Raynaud F, Schneider R, Poeschke O, Blaukat A, Workman P, Schiemann K, Eccles SA, Wienke D, Blagg J. A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. Nat Chem Biol. 2015 Dec;11(12):973-80. doi: 10.1038/nchembio.1952. Epub 2015 Oct 26. PubMed PMID: 26502155; PubMed Central PMCID: PMC4677459.
2. Mallinger A, Crumpler S, Pichowicz M, Waalboer D, Stubbs M, Adeniji-Popoola O, Wood B, Smith E, Thai C, Henley AT, Georgi K, Court W, Hobbs S, Box G, Ortiz-Ruiz MJ, Valenti M, De Haven Brandon A, TePoele R, Leuthner B, Workman P, Aherne W, Poeschke O, Dale T, Wienke D, Esdar C, Rohdich F, Raynaud F, Clarke PA, Eccles SA, Stieber F, Schiemann K, Blagg J. 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. doi: 10.1021/jm501436m. Epub 2015 Feb 13. PubMed PMID: 25680029.

Products are for research use only. Not for human use.