Discovery of Selective Small-Molecule Inhibitors for the β-Catenin/T-Cell Factor Protein-Protein Interaction through the Optimization of the Acyl Hydrazone Moiety
Discovery of Selective Small-Molecule Inhibitors for the β-Catenin/T-Cell Factor Protein-Protein Interaction through the Optimization of the Acyl Hydrazone Moiety
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DOI：
10.1021/acs.jmedchem.5b00223
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发表时间：
2015-06-11
影响因子：
7.3
通讯作者：
Ji, Haitao
中科院分区：
文献类型：
--
作者：
Catrow, J. Leon;Zhang, Yongqiang;Ji, Haitao
酰腙是发现生物活性小分子的重要官能团。该官能团也被认为是泛测定干扰结构。在这项研究中，一个新的小分子抑制剂的β-连环蛋白/Tcf蛋白质-蛋白质相互作用（PPI），ZINC 02092166，通过AlphaScreen和FP检测。该化合物含有酰基腙基团，并且在基于细胞的测定中表现出比生物化学测定更高的抑制活性。抑制剂优化导致化学稳定的衍生物，破坏β-连环蛋白/Tcf PPI。通过定点突变和构效关系研究对新抑制剂的结合模式进行了表征。这一系列具有新支架的抑制剂对β-catenin/Tcf表现出双重选择性，优于β-catenin/cadherin和β-catenin/APC PPI。该系列的一种衍生物抑制典型的Wnt信号传导，下调Wnt靶基因的表达，并抑制癌细胞的生长。该化合物代表了开发有效和选择性β-连环蛋白/Tcf抑制剂的坚实起点。
Acyl hydrazone is an important functional group for the discovery of bioactive small molecules. This functional group is also recognized as a pan assay interference structure. In this study, a new small-molecule inhibitor for the beta-catenin/Tcf protein-protein interaction (PPI), ZINC02092166, was identified through AlphaScreen and FP assays. This compound contains an acyl hydrazone group and exhibits higher inhibitory activities in cell-based assays than biochemical assays. Inhibitor optimization resulted in chemically stable derivatives that disrupt the beta-catenin/Tcf PPI. The binding mode of new inhibitors was characterized by site-directed mutagenesis and structure-activity relationship studies. This series of inhibitors with a new scaffold exhibits dual selectivity for beta-catenin/Tcf over beta-catenin/cadherin and beta-catenin/APC PPIs. One derivative of this series suppresses canonical Wnt signaling, downregulates the expression of Wnt target genes, and inhibits the growth of cancer cells. This compound represents a solid starting point for the development of potent and selective beta-catenin/Tcf inhibitors.