Discovery of Potent, Orally Bioavailable, Small-Molecule Inhibitors of WNT Signaling from a Cell-Based Pathway Screen

作者：Mallinger Aurelie; 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; Brandon Alexis De Haven; TePoele Robert; Leuthner Birgitta; Workman Paul; Aherne Wynne; Poeschke Oliver; Dale Trevor; Wienke Dirk; Esdar Christina; Rohdich Felix; Raynaud Florence; Clarke Paul A

来源：Journal of Medicinal Chemistry, 2015, 58(4): 1717-1735.

DOI：10.1021/jm501436m

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.

• 出版日期2015-2-26