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

Abstract

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 IC 50 (0.72 μM) in a competitive fluorescence polarization assay and a K D 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.

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

“…Bienz’s group identified carnosic acid ( 1 , Figure S1) with a K i value of 3.3 μM in the ELISA assay. , Ji’s group has identified and developed CP-868388 ( 2 ), PNPB-22 ( 3 ), PNPB-29 ( 4 ), and ZL3138 ( 5 ), which had inhibitory K i values of 11, 2.1, 0.47, and 1.2 μM, respectively. Apart from this, using CP-868388 ( 2 ) as the hit for structural modification and optimization, Ji’s group reported CPPAA-30 ( 6 ), ZW4864 ( 7 ), and 8 with β-catenin/BCL9 inhibitory K i values of 3.60, 0.87, and 3.40 μM, respectively. − Similarity to Ji’s group, Zhang’s group also discovered 9 based on CP-868388 ( 2 ), which had a β-catenin/BCL9 inhibitory IC 50 value of 0.72 μM in the competitive fluorescence polarization (FP) and a K d value of 0.26 μM in the SPR assay . Meanwhile, Shen designed and optimized 10 , which disrupted β-catenin/BCL9 interactions in the protein binding assay and living cells …”