Is β-Catenin a Druggable Target for Cancer Therapy?

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) 2018-08, Vol.43 (8), p.623-634
• Main Authors: Cui, Can, Zhou, Xianglian, Zhang, Weidong, Qu, Yi, Ke, Xisong
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; beta Catenin - drug effects; beta Catenin - metabolism; cancer; druggability; Humans; interaction in vivo; intrinsically disordered protein region; Intrinsically Disordered Proteins - metabolism; Neoplasms - drug therapy; Neoplasms - metabolism; protein depletion; Wnt Signaling Pathway - drug effects; β-catenin
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2018.06.003

Mutations of canonical Wnt signaling pathway genes frequently occur in cancer and lead to abnormal accumulation of the key effector β-catenin. Over the past decades, a number of Wnt inhibitors have been identified through high-throughput screenings, however, very few of them target β-catenin directly, raising questions regarding its druggability. Here, we review Wnt inhibitors with a focus on small molecules that directly bind β-catenin, discuss the druggability of β-catenin, and why it has rarely been targeted, especially in the cellular context. We also propose strategies to develop small molecule binding and depleting cellular β-catenin, which are generally applicable to other difficult-to-drug or yet-to-be-drugged targets. As an oncogenic transcription factor, β-catenin was conventionally considered as an undruggable target. However, recent discoveries of small molecules that directly bind to β-catenin suggest that β-catenin is a potentially druggable target that is yet to be drugged. Purified recombinant protein is usually required for measuring binding to a ligand, while the conformation could be different from the native protein because it may lack post-translational modifications or endogenous interacting partners. The newly developed microscale thermophoresis technology allows determination of the physical binding between a small molecule and a cellular protein in cell lysate. For small molecules that directly bind proteins without inhibitory effects, it is useful to utilize an emerging protein depletion strategy that links the protein of interest to the endogenous protein degradation machinery.