Inhibition of Wnt Signaling Using Axin Peptidomimetics through Direct Targeting of β-Catenin

Intracellular protein-protein interactions (PPIs) are attractive yet challenging therapeutic targets, particularly for signaling mediators such as β-catenin, which lack canonical druggable sites. As a central effector of the oncogenic Wnt/β-catenin pathway, β-catenin drives cancer progression through multiple PPIs, yet its shallow binding interfaces have impeded direct pharmacological inhibition. To address this limitation, we developed d-sulfonyl-γ-AApeptides─structurally stabilized peptidomimetics that efficiently mimic the α-helical protein domain of Axin to disrupt the transcriptional complex of β-catenin. These synthetic peptidic foldamers exhibit high-affinity binding to β-catenin, effectively competing with TCF4 and inhibiting the downstream Wnt signaling pathway. Combining exceptional resistance to proteolytic degradation and efficient cellular uptake, the inhibitors demonstrate pathway-selective activity, specifically reducing viability in Wnt-dependent cancer cells, leading to potent suppression of oncogenic transcription. This work not only introduces a novel therapeutic strategy for Wnt-driven cancers but also demonstrates a generalizable framework for targeting challenging PPIs through rational peptidomimetic design.