1661839-45-7

Basic information

• Product Name: CCT251545
• Synonyms: CCT251545;8-[3-Chloro-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-4-pyridinyl]-2,8-diazaspiro[4.5]decan-1-one;8-(3-chloro-5-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyridin-4-yl)-2,8-diazaspiro[4.5]decan-1-one
• CAS NO: 1661839-45-7
• Molecular Formula: C23H24ClN5O
• Molecular Weight: 421.92256
• Mol File: 1661839-45-7.mol
• Article Data: 2

Chemical Properties

• Boiling Point: 709.7±60.0 °C(Predicted)
• Appearance: /
• Density: 1.37±0.1 g/cm3(Predicted)
• Storage Temp.: Inert atmosphere,Store in freezer, under -20°C
• Solubility: ≥42.2 mg/mL in DMSO; insoluble in H2O; ≥2.33 mg/mL in EtOH with ultrasonic
• PKA: 15.81±0.20(Predicted)
• CAS DataBase Reference: CCT251545(CAS DataBase Reference)
• NIST Chemistry Reference: CCT251545(1661839-45-7)
• EPA Substance Registry System: CCT251545(1661839-45-7)

Safety Data

• Hazardous Substances Data: 1661839-45-7(Hazardous Substances Data)

Usage

Description

CCT251545 is an orally bioavailable inhibitor of Wnt signaling (IC50 = 5 nM). It is a potent and selective inhibitor of the human mediator complex-associated protein kinases Cdk8 and Cdk19. Through its effects on Cdk8 and Cdk19, CCT251545 alters Wnt pathway-regulated gene expression. It reduces tumor growth in COLO 205 human colon cancer xenografts after oral dosing (70 mg/kg bid) and in Wnt-dependent tumors.

Uses

CCT251545 is a potent inhibitor of WNT signaling with good oral pharmacokinetics.

references

[1]. mallinger a, crumpler s, pichowicz m, et al. discovery of potent, orally bioavailable, small-molecule inhibitors of wnt signaling from a cell-based pathway screen. j med chem, 2015, 58(4): 1717-1735.[2]. dale t, clarke pa, esdar c, et al. a selective chemical probe for exploring the role of cdk8 and cdk19 in human disease. nat chem biol, 2015, 11(12): 973-980.

Upstream product

• 637-87-6 1-Chloro-4-iodobenzene 
• 73583-39-8 3-bromo-5-chloropyridine 
• 1607838-14-1 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole 
• 1001056-83-2 3-bromo-4,5-dichloro-pyridine 

Relevant articles and documents

Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen

WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.