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,Journal of Medicinal Chemistry

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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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-01-11 , DOI: 10.1021/acs.jmedchem.2c01568
Hao Zhang _{1,

2} , Chenglong Liu ₁ , Qiushi Chen _{2,

3} , Li-An Shen ₁ , Wenting Xiao _{1,

2} , Jiayi Li _{2,

3} , Yonghui Wang ₁ , Di Zhu _{1,

4} , Qingwei Zhang ₂ , Jianqi Li ₂

Affiliation

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 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.

中文翻译：

发现新型 3-苯基哌啶衍生物靶向 β-连环蛋白/B 细胞淋巴瘤 9 的相互作用，作为单一药物并与抗 PD-1 抗体联合治疗结直肠癌

直接破坏 β-连环蛋白/B 细胞淋巴瘤 9 (BCL9) 蛋白-蛋白相互作用 (PPI) 是一种通过抑制致癌 Wnt 活性来治疗结直肠癌 (CRC) 的潜在策略。在此，合成了一系列 3-苯基哌啶衍生物，并将其作为 β-连环蛋白/BCL9 PPI 抑制剂进行评估。其中，化合物41在竞争性荧光偏振测定中显示出最佳的 IC _{50 (0.72 μM)，对 β-catenin 蛋白的}K _D值为 0.26 μM。该化合物选择性地抑制 CRC 细胞的生长，抑制 Wnt 信号反式激活，并下调致癌 Wnt 靶基因表达。体内，41显示出有效的抗 CRC 活性并促进细胞毒性 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，41与抗 PD-1 抗体 (Ab) 的组合有效增强了抗 CRC 疗效，首次验证了小分子 β-catenin/BCL9 PPI 抑制剂和抗 PD-1 Ab 在体内的疗效组合。

更新日期：2023-01-11

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