Dr Kenneth Ewan
Telephone:+44(0)29 208 79073
Location:Cardiff School of Biosciences, The Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX
CELL-BASED SCREENING FOR INHIBITORS OF THE WNT SIGNALLING PATHWAY
Oncogenic deregulation of the Wnt signalling pathway is a causal factor in the initiation of cancer in a diverse range of tissues including the colon, breast and liver. To identify small-molecule inhibitors of Wnt signaling as potential therapeutics, a diverse chemical library at the Cancer Research UK Centre for Cancer Therapeutics was screened using a transcription factor reporter cell line in which the activity of the pathway was induced at the level of Disheveled protein. A series of deconvolution studies was used to focus on three compound series that selectively killed cancer cell lines with constitutive Wnt signaling ( Cancer Res  70, 5963–73 ). Activities of the compounds included the ability to induce degradation of β-catenin that had been stabilized by a glycogen synthase kinase-3 (GSK-3) inhibitor. This initial screen illustrated a practical approach to identify small-molecule inhibitors of Wnt signaling which now is being used for a full scale drug discovery project in collaboration with Merck-Serono, the Institute of Cancer Research and Cancer Research Technology. My present work includes mouse PD biomarker and efficacy assays, cultured intestinal organoid growth and biomarker assays.