1区 · 医学
Article
作者: Court, William ; Mallinger, Aurélie ; Raynaud, Florence ; Eccles, Suzanne A. ; Stieber, Frank ; Box, Gary ; Rohdich, Felix ; Clarke, Paul A. ; Wood, Bozena ; Adeniji-Popoola, Olajumoke ; Waalboer, Dennis ; Esdar, Christina ; Aherne, Wynne ; Schiemann, Kai ; Workman, Paul ; Pichowicz, Mark ; Thai, Ching ; Leuthner, Birgitta ; Dale, Trevor ; Wienke, Dirk ; Crumpler, Simon ; TePoele, Robert ; Georgi, Katrin ; Poeschke, Oliver ; Smith, Elizabeth ; Henley, Alan T. ; Ortiz-Ruiz, Maria-Jesus ; Hobbs, Steve ; Stubbs, Mark ; Blagg, Julian ; Valenti, Melanie ; De Haven Brandon, Alexis
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.