Disruption of β-Catenin/B-Cell Lymphoma 9 Protein–Protein Interaction Using Heterogeneous Peptidomimetic Foldamers

Aberrant activation of the Wnt/β-catenin-signaling pathway is closely linked to the development and progression of colorectal cancer (CRC) and other malignancies. Targeting and inhibiting this pathway has proved to be a promising approach for the development of antitumor drugs. In this study, we designed and synthesized a series of helical 1:1 α/sulfonyl-γ-AApeptide inhibitors aiming to disrupt the interaction between β-catenin and BCL9. Circular dichroism spectroscopy and modeling studies suggest that these 1:1 α/sulfonyl-γ-AApeptides adopt a right-handed helical conformation and effectively mimic the crucial side chains of BCL9, with the most potent compound exhibiting nanomolar affinity for β-catenin. Notably, these peptidomimetics possess excellent permeability, allowing them to penetrate CRC cancer cells, downregulate Wnt target genes, disrupt the cellular β-catenin/BCL9 protein-protein interaction (PPI), and significantly reduce the proliferation of Wnt-hyperactive cell lines. Furthermore, these hybrid peptidomimetics demonstrate enhanced serum stability, which augments their potential as therapeutic agents for future applications. In addition, this study paves a new way to modulate a myriad of PPIs.