Targeting the Wnt signalling pathway


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Trevor Dale

Cardiff University, UK

Abstract

Targeting 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. The ‘core components’ of the Wnt signalling pathway make relatively unpromising drug targets for conventional small molecule drug screens. To overcome this difficulty, we have used a cell-based screen to identify small compounds that block Wnt signalling. We have combined this approach with a systematic series of deconvolution assays aimed at identifying the molecular targets of the hit compounds.

A library of 68,000 compounds was screened leading to the identification of a small number of drugable hits. Primary hits and analogues were found to have activity in tumour cell lines and in zebrafish embryos. Transfection-based approaches were used to identify the point of action of the compounds in the Wnt pathway. The current set of 4 leads include two that operate at the level of β-catenin and two that work at the level of TCF.