Getting a Grip on the Undrugged: Targeting β-Catenin with Fragment-Based Methods

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Aberrant WNT pathway activation, characterized by nuclear beta-catenin accumulation, drives cancer progression.
• Mutations in the APC tumor suppressor gene impair beta-catenin degradation, promoting its nuclear translocation and oncogenic activity.

Purpose of the Study:

• To report the fragment-based discovery of a small molecule binder for beta-catenin.
• To elucidate the binding mode of the identified small molecule using X-ray crystallography.

Main Methods:

• Fragment-based drug discovery approach.
• Iterative virtual screening and Nuclear Magnetic Resonance (NMR) screening.
• X-ray crystallography for structural elucidation of the beta-catenin-ligand complex.

Main Results:

• Identified a small molecule binder for beta-catenin, overcoming initial screening challenges.
• Determined the binding site to be between armadillo repeats two and three, adjacent to BCL9 and TCF4 interaction sites.
• Structural data and assays suggest limited potential for direct protein-protein interaction inhibition but offer a basis for PROTAC development.

Conclusions:

• The discovered beta-catenin binder provides a starting point for therapeutic strategies.
• Structural insights pave the way for developing beta-catenin proteolysis targeting chimeras (PROTACs) as a novel therapeutic modality.