Structure-Based Discovery of a Novel Inhibitor Targeting the 尾-Catenin/Tcf4 Interaction

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• 作者：Wang Tian ; Xiaofeng Han ; Maocai Yan ; Yan Xu ; Srinivas Duggineni ; Nan Lin ; Guifen Luo ; Yan Michael Li ; Xiaobing Han ; Ziwei Huang ; Jing An
• 刊名：Biochemistry
• 出版年：2012
• 出版时间：January 17, 2012
• 年：2012
• 卷：51
• 期：2
• 页码：724-731
• 全文大小：442K
• 年卷期：v.51,no.2(January 17, 2012)
• ISSN：1520-4995

文摘

Overactivation or overexpression of 尾-catenin in the Wnt (wingless) signaling pathway plays an important role in tumorigenesis. Interaction of 尾-catenin with T-cell factor (Tcf) DNA binding proteins is a key step in the activation of the proliferative genes in response to upstream signals of this Wnt/尾-catenin pathway. Recently, we identified a new small molecule inhibitor, named BC21 (C₃₂H₃₆Cl₂Cu₂N₂O₂), which effectively inhibits the binding of 尾-catenin with Tcf4-derived peptide and suppresses 尾-catenin/Tcf4 driven reporter gene activity. This inhibitor decreases the viability of 尾-catenin overexpressing HCT116 colon cancer cells that harbor the 尾-catenin mutation, and more significantly, it inhibits the clonogenic activity of these cells. Down-regulation of c-Myc and cyclin D1 expression, the two important effectors of the Wnt/尾-catenin signaling, is confirmed by treating HCT116 cells with BC21. This compound represents a new and modifiable potential anticancer candidate that targets 尾-catenin/Tcf-4 interaction.