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Published on: December 20, 2017
Getting a Grip on the Undrugged: Targeting β-Catenin with Fragment-Based Methods
Dirk Kessler1, Moriz Mayer1, Stephan K Zahn1
1Boehringer Ingelheim RCV GmbH & Co KG, Dr.-Boehringer-Gasse 5-11, 1121, Vienna, Austria.
Abstract:
Aberrant WNT pathway activation, leading to nuclear accumulation of β-catenin, is a key oncogenic driver event. Mutations in the tumor suppressor gene APC lead to impaired proteasomal degradation of β-catenin and subsequent nuclear translocation. Restoring cellular degradation of β-catenin represents a potential therapeutic strategy. Here, we report the fragment-based discovery of a small molecule binder to β-catenin, including the structural elucidation of the binding mode by X-ray crystallography. The difficulty in drugging β-catenin was confirmed as the primary screening campaigns identified only few and very weak hits. Iterative virtual and NMR screening techniques were required to discover a compound with sufficient potency to be able to obtain an X-ray co-crystal structure. The binding site is located between armadillo repeats two and three, adjacent to the BCL9 and TCF4 binding sites. Genetic studies show that it is unlikely to be useful for the development of protein-protein interaction inhibitors but structural information and established assays provide a solid basis for a prospective optimization towards β-catenin proteolysis targeting chimeras (PROTACs) as alternative modality.
Insights
Researchers discovered a small molecule that binds to beta-catenin, a protein involved in cancer. This finding provides a foundation for developing new cancer therapies targeting beta-catenin degradation.
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.
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