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

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Oncology

Background:

• Intracellular protein-protein interactions (PPIs) are challenging therapeutic targets, especially for signaling proteins like β-catenin.
• β-catenin is a key mediator in the oncogenic Wnt/β-catenin pathway, driving cancer progression through multiple PPIs.
• Shallow binding interfaces of β-catenin have hindered direct pharmacological inhibition.

Purpose of the Study:

• To develop novel peptidomimetics targeting β-catenin's PPIs.
• To create inhibitors that disrupt the β-catenin/TCF4 transcriptional complex.
• To establish a generalizable framework for targeting difficult PPIs.

Main Methods:

• Design and synthesis of d-sulfonyl-γ-AApeptides, stabilized peptidomimetics mimicking the Axin α-helical domain.
• Assessment of high-affinity binding to β-catenin and competition with TCF4.
• Evaluation of proteolytic degradation resistance, cellular uptake, and pathway-selective activity in Wnt-dependent cancer cells.

Main Results:

• Developed d-sulfonyl-γ-AApeptides with high-affinity binding to β-catenin.
• Demonstrated disruption of the β-catenin/TCF4 transcriptional complex and inhibition of Wnt signaling.
• Showcased pathway-selective reduction in viability and oncogenic transcription in Wnt-dependent cancer cells.

Conclusions:

• d-sulfonyl-γ-AApeptides represent a novel therapeutic strategy for Wnt-driven cancers.
• These inhibitors effectively target challenging PPIs by mimicking protein interfaces.
• The developed peptidomimetic design framework is generalizable for targeting other difficult PPIs.