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

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• 作者：John A. Wisniewski ; Jinya Yin ; Kevin B. Teuscher ; Min Zhang ; Haitao Ji
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：May 12, 2016
• 年：2016
• 卷：7
• 期：5
• 页码：508-513
• 全文大小：462K
• 年卷期：0
• ISSN：1948-5875

文摘

A small-molecule inhibitor with a 1,4-dibenzoylpiperazine scaffold was designed to match the critical binding elements in the β-catenin/B-cell lymphoma 9 (BCL9) protein–protein interaction interface. Inhibitor optimization led to a potent inhibitor that can disrupt the β-catenin/BCL9 interaction and exhibit 98-fold selectivity over the β-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/β-catenin-dependent cancer cells.