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

Mallinger, Aurélie, Crumpler, Simon, Pichowicz, Mark, Waalboer, Dennis, Stubbs, Mark, Adeniji-Popoola, Olajumoke, Wood, Bozena, Smith, Elizabeth, Thai, Ching, Henley, Alan T., Georgi, Katrin, Court, William, Hobbs, Steve, Box, Gary, Ortiz-Ruiz, Maria-Jesus, Valenti, Melanie, De Haven Brandon, Alexis, TePoele, Robert, Leuthner, Birgitta, Workman, Paul, Aherne, Wynne, Poeschke, Oliver, Dale, Trevor Clive ORCID:, Wienke, Dirk, Esdar, Christina, Rohdich, Felix, Raynaud, Florence, Clarke, Paul A., Eccles, Suzanne A., Stieber, Frank, Schiemann, Kai and Blagg, Julian 2015. Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen. Journal of Medicinal Chemistry 58 (4) , pp. 1717-1735. 10.1021/jm501436m

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > QR Microbiology
Publisher: American Chemical Society
ISSN: 0022-2623
Last Modified: 22 Jun 2023 10:00

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