- Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen
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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.
- Adeniji-Popoola, Olajumoke,Aherne, Wynne,Blagg, Julian,Box, Gary,Clarke, Paul A.,Court, William,Crumpler, Simon,Dale, Trevor,De Haven Brandon, Alexis,Eccles, Suzanne A.,Esdar, Christina,Georgi, Katrin,Henley, Alan T.,Hobbs, Steve,Leuthner, Birgitta,Mallinger, Aurlie,Ortiz-Ruiz, Maria-Jesus,Pichowicz, Mark,Poeschke, Oliver,Raynaud, Florence,Rohdich, Felix,Schiemann, Kai,Smith, Elizabeth,Stieber, Frank,Stubbs, Mark,Tepoele, Robert,Thai, Ching,Valenti, Melanie,Waalboer, Dennis,Wienke, Dirk,Wood, Bozena,Workman, Paul
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p. 1717 - 1735
(2015/04/27)
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- PYRIDYL PIPERIDINES
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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.
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