Structure-Based Design of 1,4-Dibenzoylpiperazines as β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction Inhibitors

被引：34
作者：
Wisniewski, John A. [1 ]
Yin, Jinya [1 ]
Teuscher, Kevin B. [1 ]
Zhang, Min [1 ]
Ji, Haitao [1 ]
机构：
[1] Univ Utah, Ctr Cell & Genome Sci, Dept Chem, Salt Lake City, UT 84112 USA
来源：
ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 05期
关键词：
Wnt signaling beta-Catenin; B-cell lymphoma 9; protein-protein interactions; inhibitor; selectivity; COLORECTAL-CANCER; BINDING PROTEIN; PROGRESSION; ACTIVATION; PORCUPINE; BCL9-2; TARGET; SITE; AXIN;
D O I：
10.1021/acsmedchemlett.5b00284
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A small-molecule inhibitor with a 1,4-dibenzoylpiperazine scaffold was designed to match the critical binding elements in the beta-catenin/B-cell lymphoma 9 (BCL9) protein protein interaction interface. Inhibitor optimization led to a potent inhibitor that can disrupt the beta-catenin/BCL9 interaction and exhibit 98-fold selectivity over the beta-catenin/cadherin interaction. The binding mode of new inhibitors was characterized by structure activity relationships and site-directed mutagenesis studies. Cell-based studies demonstrated that this series of inhibitors can selectively suppress canonical Wnt signaling and inhibit growth of Wnt/beta-catenin-dependent cancer cells.
引用
收藏
页码：508 / 513
页数：6
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