Researchers designed novel bicyclic helical peptides that bind the flat, cavity-lacking surface of the oncogene β-catenin with high affinity, achieving single-digit micromolar activity in cell-based assays.
Single-digit μM activityBicyclic peptide inhibitor achieves cell-based activity against the notoriously difficult cancer target β-catenin
What the researchers found
A bicyclic stitched peptide with unprecedented crosslink architecture was designed to bind β-catenin, with the binding mode confirmed by crystal structure and cell-based activity reaching single-digit micromolar inhibition.
Why it matters
β-catenin is implicated in colorectal, breast, liver, and many other cancers but has resisted drug development for decades. These smaller peptide inhibitors represent a potential breakthrough for targeting this challenging oncogene.
The numbers in context
The bicyclic peptides are considerably smaller than previous β-catenin inhibitors while maintaining high binding affinity.
How the study worked
Structure-based design starting from the Axin α-helical binding motif, followed by sequence maturation, bicyclization with novel crosslink architecture, X-ray crystallography to confirm binding, and cell-based assay validation.
Who was studied
Biochemical characterization of designed peptides against β-catenin protein
What this study cannot tell us
Early-stage drug design — demonstrated binding and cell-based activity but no in vivo testing. Cell penetration and metabolic stability need further optimization. Single-digit micromolar potency may need improvement for therapeutic use.
How to read the evidence
Preliminary evidence — proof-of-concept drug design study with in vitro and cell-based validation but no animal testing.
When this study was published
Published in 2024, representing the cutting edge of constrained peptide drug design for cancer targets.
The bigger picture
Many cancer-driving proteins have flat surfaces that resist conventional drug design. Constrained peptides — like the bicyclic helical structures developed here — represent a growing toolbox for tackling these 'undruggable' targets, potentially opening new therapeutic avenues across oncology.
Questions still open
- Can these bicyclic peptides be further optimized for nanomolar potency and oral bioavailability?
- Would they be effective in animal cancer models with activated Wnt/β-catenin signaling?
- Could this stitched peptide design approach be applied to other flat protein-protein interaction surfaces in cancer?
Common questions
Why is β-catenin so hard to target with drugs?
What makes these peptides different from previous β-catenin inhibitors?
Read the original research
Structure-Based Design of Bicyclic Helical Peptides That Target the Oncogene β-Catenin.
Angewandte Chemie (International ed. in English), 63(47), e202411749
Citation
Yeste-Vázquez, Alejandro; Paulussen, Felix M; Wendt, Mathias; Klintrot, Rasmus; Schulte, Clemens; Wallraven, Kerstin; van Gijzel, Lieke; Simeonov, Boris; van der Gaag, Maurice; Gerber, Alan; Maric, Hans M; Hennig, Sven; Grossmann, Tom N. (2024). Structure-Based Design of Bicyclic Helical Peptides That Target the Oncogene β-Catenin.. Angewandte Chemie (International ed. in English), 63(47), e202411749. https://doi.org/10.1002/anie.202411749