School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, 285 Gebai Ni Road, Shanghai 201203, China.
J Med Chem. 2023 Jan 26;66(2):1349-1379. doi: 10.1021/acs.jmedchem.2c01568. Epub 2023 Jan 11.
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 showed the best IC (0.72 μM) in a competitive fluorescence polarization assay and a 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, 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 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.
直接破坏β-连环蛋白/淋巴瘤 9（BCL9）蛋白-蛋白相互作用（PPI）是通过抑制致癌 Wnt 活性来治疗结直肠癌（CRC）的一种潜在策略。在此，合成了一系列 3-苯基哌啶衍生物，并将其评估为β-连环蛋白/BCL9 PPI 抑制剂。其中，化合物在竞争性荧光偏振测定中显示出最好的 IC（0.72μM）值，对β-连环蛋白蛋白的 值为 0.26μM。该化合物选择性地抑制 CRC 细胞的生长，抑制 Wnt 信号转导的激活，并下调致癌 Wnt 靶基因的表达。在体内， 表现出强大的抗 CRC 活性，促进细胞毒性 T 淋巴细胞的浸润和功能，同时减少调节性 T 细胞（Tregs）的浸润。此外， 与抗 PD-1 抗体（Ab）的联合使用有效地增强了抗 CRC 疗效，首次验证了小分子β-连环蛋白/BCL9 PPI 抑制剂与抗 PD-1 Ab 联合在体内的疗效。
