Discovery of Novel 1-Phenylpiperidine Urea-Containing Derivatives Inhibiting β-Catenin/BCL9 Interaction and Exerting Antitumor Efficacy through the Activation of Antigen Presentation of cDC1 Cells

Aberrant activation of the Wnt/β-catenin signaling is associated with tumor development, and blocking β-catenin/BCL9 is a novel strategy for oncogenic Wnt/β-catenin signaling. Herein, we presented two novel β-catenin variations and exposed conformational dynamics in several β-catenin crystal structures at the BCL9 binding site. Furthermore, we identified a class of novel urea-containing compounds targeting β-catenin/BCL9 interaction. Notably, the binding modalities of inhibitors were greatly affected by the conformational dynamics of β-catenin. Among them,