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.

典型的Wnt信号通路基因的突变在癌症中经常发生，并导致关键效应子β-catenin异常积聚。在过去的几十年中，通过高通量筛选已鉴定出多种Wnt抑制剂，但是，只有极少数的Wnt抑制剂直接靶向β-catenin，这引发了有关其可药物性的问题。在这里，我们综述了Wnt抑制剂，重点研究了直接结合β-catenin的小分子，讨论了β-catenin的可药用性，以及为什么它很少被靶向，尤其是在细胞环境中。我们还提出了发展小分子结合和消耗细胞β-catenin的策略，这些策略通常适用于其他难以毒品或尚未毒品的目标。