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

Journal of medicinal chemistry (2015-02-14)
Aurélie Mallinger, Simon Crumpler, Mark Pichowicz, Dennis Waalboer, Mark Stubbs, Olajumoke Adeniji-Popoola, Bozena Wood, Elizabeth Smith, Ching Thai, Alan T Henley, Katrin Georgi, William Court, Steve Hobbs, Gary Box, Maria-Jesus Ortiz-Ruiz, Melanie Valenti, Alexis De Haven Brandon, Robert TePoele, Birgitta Leuthner, Paul Workman, Wynne Aherne, Oliver Poeschke, Trevor Dale, Dirk Wienke, Christina Esdar, Felix Rohdich, Florence Raynaud, Paul A Clarke, Suzanne A Eccles, Frank Stieber, Kai Schiemann, Julian Blagg
ABSTRACT

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.

MATERIALS
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Product Description

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