1661839-45-7

Usage

Uses

Used in Pharmaceutical Industry:
CCT251545 is used as an anticancer agent for its potent inhibition of WNT signaling, which plays a crucial role in the development and progression of various types of cancer. Its good oral pharmacokinetics make it a promising candidate for the development of targeted cancer therapies.
Used in Cancer Research:
CCT251545 is used as a research tool for studying the role of Wnt signaling and the mediator complex-associated protein kinases Cdk8 and Cdk19 in cancer biology. It helps researchers understand the molecular mechanisms underlying tumor growth and the potential of targeting these pathways for therapeutic intervention.
Used in Drug Development:
CCT251545 is used in the development of novel cancer therapies targeting the Wnt signaling pathway. Its potent inhibition of Cdk8 and Cdk19, along with its ability to reduce tumor growth in preclinical models, makes it a valuable compound for further optimization and development as a potential cancer treatment.

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.

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Relevant academic research and scientific papers

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.

PYRIDYL PIPERIDINES

The invention provides novel substituted pyridyl piperidine compounds according to Formula (I) which are Wnt pathway inhibitors, their manufacture and use for the treatment of hyperproliferative diseases such as cancer, inflammatory or degenerative diseases.