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, 28 had a strong
affinity for β-catenin (Kd = 82
nM), the most potent inhibitor reported. In addition, 13 and 35 not only activate T cells but also promote the
antigen presentation of cDC1, showing robust antitumor efficacy in
the CT26 model. Collectively, our study demonstrated a series of potent
small-molecule inhibitors targeting β-catenin/BCL9, which can
enhance antigen presentation and activate cDC1 cells, delivering a
potential strategy for boosting innate and adaptive immunity to overcome
immunotherapy resistance.