Targeting the Transcriptional Hub β-Catenin Using Stapled Peptides

This chapter describes a design-based approach for the development of cell-permeable protein-protein interactions (PPI) inhibitors directly targeting β-catenin. The design process described herein relies on a combination of optimization strategies utilizing directed evolution by phage display and synthetic pharmaceuticalization via α-helix stapling. Biochemical, biophysical, and cellular characterization of the stapled peptide inhibitor, plus an X-ray structure of it bound to β-catenin all have provided insights into the molecular basis of Wingless and INT-1 (Wnt) pathway antagonism by this novel agent. The biological appeal of β-catenin-T-cell factor/lymphoid enhancer factor (TCF/LEF) interactions is counterbalanced by the chemical intractability of intracellular PPIs as targets, with transcription factors being considered among the most intractable of all PPI targets, owing to their extended interaction interfaces. The chapter describes an approach in which the formation of the transcriptional activator complex between β-catenin and TCF4 is competitively inhibited by direct targeting of β-catenin.