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.