期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 4, 页码 1717-1735出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm501436m
关键词
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资金
- Cancer Research UK [C309/A11566]
- NHS
- Biotechnology and Biological Sciences Research Council [BB/D00117X/1] Funding Source: researchfish
- Cancer Research UK [11566, 15937] Funding Source: researchfish
- BBSRC [BB/D00117X/1] Funding Source: UKRI
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.
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