Inhibition of nuclear Wnt signalling: challenges of an elusive target for cancer therapy

The highly conserved Wnt signalling pathway plays an important role in embryonic development and disease pathogenesis, most notably cancer. The 'canonical' or beta-catenin-dependent Wnt signal initiates at the cell plasma membrane with the binding of Wnt proteins to Frizzled: LRP5/LRP6 receptor complexes and is mediated by the translocation of the transcription co-activator protein, beta-catenin, into the nucleus. beta-Catenin then forms a complex with T-cell factor (TCF)/lymphoid enhancer binding factor (LEF) transcription factors to regulate multiple gene programmes. These programmes play roles in cell proliferation, migration, vasculogenesis, survival and metabolism. Mutations in Wnt signalling pathway components lead to constitutively active Wnt signalling that drives aberrant expression of these programmes and development of cancer. It has been a longstanding and challenging goal to develop therapies that can interfere with the TCF/LEF-beta-catenin transcriptional complex. This review will focus on the (i) structural considerations for targeting the TCF/LEF-beta-catenin and co-regulatory complexes in the nucleus, (ii) current molecules that directly target TCF/LEF-beta-catenin activity and (iii) ideas for targeting newly discovered components of the TCF/LEF-beta-catenin complex and/or downstream gene programmes regulated by these complexes.