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.

细胞内蛋白质-蛋白质相互作用（protein–protein interactions, PPIs）是一类兼具吸引力与挑战性的治疗靶点，对于β-连环蛋白（β-catenin）这类缺乏经典可药化结合位点的信号介质而言尤为如此。作为致癌性Wnt/β-连环蛋白信号通路的核心效应分子，β-连环蛋白可通过多种蛋白质-蛋白质相互作用驱动癌症进展，但其结合界面较浅的特性阻碍了直接的药理学抑制。为解决这一局限，我们开发了d-磺酰基-γ-AA肽模拟物（d-sulfonyl-γ-AApeptides）——这类结构稳定的拟肽可高效模拟轴蛋白（Axin）的α螺旋蛋白结构域，从而破坏β-连环蛋白的转录复合物。该类合成肽类折叠体对β-连环蛋白具有高亲和力结合活性，可有效竞争性结合T细胞因子4（TCF4）并抑制下游Wnt信号通路。结合优异的抗蛋白水解降解能力与高效细胞摄取特性，这类抑制剂展现出通路选择性活性，可特异性降低Wnt依赖型癌细胞的存活率，进而强效抑制致癌转录。本研究不仅为Wnt驱动型癌症提供了一种全新的治疗策略，同时也为通过理性拟肽设计靶向高挑战性蛋白质-蛋白质相互作用提供了可推广的研究框架。