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Discovery of 2-(3-(3-Carbamoylpiperidin-1-yl)phenoxy)acetic Acid Derivatives as Novel Small-Molecule Inhibitors of the β-Catenin/B-Cell Lymphoma 9 Protein–Protein Interaction
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-04-26 , DOI: 10.1021/acs.jmedchem.1c00046 Zhen Wang 1 , Min Zhang 1 , Wen Luo 1 , Yongqiang Zhang 2 , Haitao Ji 1, 3
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-04-26 , DOI: 10.1021/acs.jmedchem.1c00046 Zhen Wang 1 , Min Zhang 1 , Wen Luo 1 , Yongqiang Zhang 2 , Haitao Ji 1, 3
Affiliation
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The β-catenin/B-cell lymphoma 9 (BCL9) protein–protein interaction (PPI) is a potential target for the suppression of hyperactive Wnt/β-catenin signaling that is vigorously involved in cancer initiation and development. Herein, we describe the medicinal chemistry optimization of a screening hit to yield novel small-molecule inhibitors of the β-catenin/BCL9 interaction. The best compound 30 can disrupt the β-catenin/BCL9 interaction with a Ki of 3.6 μM in AlphaScreen competitive inhibition assays. Cell-based experiments revealed that 30 selectively disrupted the β-catenin/BCL9 PPI, while leaving the β-catenin/E-cadherin PPI unaffected, dose-dependently suppressed Wnt signaling transactivation, downregulated oncogenic Wnt target gene expression, and on-target selectively inhibited the growth of cancer cells harboring aberrant Wnt signaling. This compound with a new chemotype can serve as a lead compound for further optimization of inhibitors for β-catenin/BCL9 PPI.
中文翻译:
发现2-(3-(3-氨基甲酰基哌啶-1-基)苯氧基)乙酸衍生物是β-Catenin/ B细胞淋巴瘤9蛋白-蛋白质相互作用的新型小分子抑制剂
β-catenin/ B细胞淋巴瘤9(BCL9)蛋白-蛋白相互作用(PPI)是抑制过度活跃的Wnt /β-catenin信号传导的潜在靶标,该信号通路强烈参与癌症的发生和发展。在这里,我们描述了筛选击中产生β-catenin/ BCL9相互作用的新型小分子抑制剂的药物化学优化。在AlphaScreen竞争抑制试验中,最佳化合物30可以以3.6μM的K i破坏β-catenin/ BCL9的相互作用。基于细胞的实验表明30选择性破坏β-catenin/ BCL9 PPI,同时保持β-catenin/ E-cadherin PPI不受影响,剂量依赖性抑制Wnt信号转激活,下调致癌Wnt靶基因表达,并按靶选择性抑制含有癌细胞的癌细胞的生长Wnt信号异常。这种具有新化学型的化合物可以用作进一步优化β-catenin/ BCL9 PPI抑制剂的先导化合物。
更新日期:2021-05-13
中文翻译:
![](https://scdn.x-mol.com/jcss/images/paperTranslation.png)
发现2-(3-(3-氨基甲酰基哌啶-1-基)苯氧基)乙酸衍生物是β-Catenin/ B细胞淋巴瘤9蛋白-蛋白质相互作用的新型小分子抑制剂
β-catenin/ B细胞淋巴瘤9(BCL9)蛋白-蛋白相互作用(PPI)是抑制过度活跃的Wnt /β-catenin信号传导的潜在靶标,该信号通路强烈参与癌症的发生和发展。在这里,我们描述了筛选击中产生β-catenin/ BCL9相互作用的新型小分子抑制剂的药物化学优化。在AlphaScreen竞争抑制试验中,最佳化合物30可以以3.6μM的K i破坏β-catenin/ BCL9的相互作用。基于细胞的实验表明30选择性破坏β-catenin/ BCL9 PPI,同时保持β-catenin/ E-cadherin PPI不受影响,剂量依赖性抑制Wnt信号转激活,下调致癌Wnt靶基因表达,并按靶选择性抑制含有癌细胞的癌细胞的生长Wnt信号异常。这种具有新化学型的化合物可以用作进一步优化β-catenin/ BCL9 PPI抑制剂的先导化合物。