Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen
- J Med Chem. 2015 Feb 26;58(4):1717-35. doi: 10.1021/jm501436m.
- 1. Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London SW7 3RP, U.K.
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.