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 K_i 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：

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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。