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

Aberrant WNT pathway activation, leading to nuclear accumulation of beta-catenin, is a key oncogenic driver event. Mutations in the tumor suppressor gene APC lead to impaired proteasomal degradation of beta-catenin and subsequent nuclear translocation. Restoring cellular degradation of beta-catenin represents a potential therapeutic strategy. Here, we report the fragment-based discovery of a small molecule binder to beta-catenin, including the structural elucidation of the binding mode by X-ray crystallography. The difficulty in drugging beta-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 beta-catenin proteolysis targeting chimeras (PROTACs) as alternative modality.

Automated summary

Aberrant activation of the WNT pathway leads to nuclear accumulation of beta-catenin, a key oncogenic event. Mutations in the APC gene impair proteasomal degradation of beta-catenin and promote its nuclear translocation. Fragment-based discovery of a small molecule binder to beta-catenin, along with elucidation of the binding mode, was achieved through X-ray crystallography.