Discovery of Novel 3‑Phenylpiperidine Derivatives Targeting the β‑Catenin/B-Cell Lymphoma 9 Interaction as a Single Agent and in Combination with the Anti-PD‑1 Antibody for the Treatment of Colorectal Cancer

Direct
disruption of the β-catenin/B-cell lymphoma 9 (BCL9)
protein–protein interaction (PPI) is a potential strategy for
colorectal cancer (CRC) treatment through inhibiting oncogenic Wnt
activity. Herein, a series of 3-phenylpiperidine derivatives were
synthesized and evaluated as β-catenin/BCL9 PPI inhibitors.
Among them, compound 41 showed the best IC50 (0.72 μM) in a competitive fluorescence polarization assay
and a KD value of 0.26 μM for the
β-catenin protein. This compound selectively inhibited the growth
of CRC cells, suppressed Wnt signaling transactivation, and downregulated
oncogenic Wnt target gene expression. In vivo, 41 showed
potent anti-CRC activity and promoted the infiltration and function
of cytotoxic T lymphocytes while decreasing the infiltration of regulatory
T-cells (Tregs). Furthermore, the combination of 41 and
the anti-PD-1 antibody (Ab) efficiently enhanced anti-CRC efficacy,
first verifying the in vivo efficacy of the small-molecule β-catenin/BCL9
PPI inhibitor and anti-PD-1 Ab in combination.