CCT251545 and Colorectal-Neoplasms

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.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Assay; Biological Availability; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Crystallography, X-Ray; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Luciferases; Mice; Models, Molecular; Molecular Structure; Pyridines; Small Molecule Libraries; Spiro Compounds; Structure-Activity Relationship; Wnt Signaling Pathway; Xenograft Model Antitumor Assays