Structure-based Discovery of Novel Small Molecule Wnt Signaling Inhibitors by Targeting the Cysteine-rich Domain of Frizzled.
Structure-based Discovery of Novel Small Molecule Wnt Signaling Inhibitors by Targeting the Cysteine-rich Domain of Frizzled.
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DOI：
10.1074/jbc.m115.673202
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发表时间：
2015-12-18
期刊：
影响因子：
--
通讯作者：
Zheng JJ
中科院分区：
文献类型：
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作者：
Lee HJ;Bao J;Miller A;Zhang C;Wu J;Baday YC;Guibao C;Li L;Wu D;Zheng JJ
Frizzled是最早发现的糖基化Wnt蛋白受体，对Wnt信号的启动至关重要。拮抗Frizzled可有效抑制多种肿瘤类型的生长。Frizzled的胞外N末端含有一个保守的富含半胱氨酸的结构域，该结构域直接与Wnt配体相互作用。使用基于结构的虚拟筛选和基于细胞的测定来鉴定可以抑制典型Wnt信号传导并且在微摩尔范围内具有低IC 50值的五种小分子。NMR实验证实，这些化合物特异性地结合到卷曲8富含半胱氨酸的结构域上的Wnt结合位点，具有亚微摩尔解离常数。我们的研究证实了靶向卷曲富含半胱氨酸结构域作为调节经典Wnt信号传导的有效方式的可行性。这些小分子可以进一步优化成更有效的治疗剂，用于通过靶向Frizzled来调节异常Wnt信号传导。
Frizzled is the earliest discovered glycosylated Wnt protein receptor and is critical for the initiation of Wnt signaling. Antagonizing Frizzled is effective in inhibiting the growth of multiple tumor types. The extracellular N terminus of Frizzled contains a conserved cysteine-rich domain that directly interacts with Wnt ligands. Structure-based virtual screening and cell-based assays were used to identify five small molecules that can inhibit canonical Wnt signaling and have low IC50 values in the micromolar range. NMR experiments confirmed that these compounds specifically bind to the Wnt binding site on the Frizzled8 cysteine-rich domain with submicromolar dissociation constants. Our study confirms the feasibility of targeting the Frizzled cysteine-rich domain as an effective way of regulating canonical Wnt signaling. These small molecules can be further optimized into more potent therapeutic agents for regulating abnormal Wnt signaling by targeting Frizzled.
DOI：
10.1007/978-1-62703-008-3_2
发表时间：
2012
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Shan, Jufang;Zheng, Jie J
通讯作者：
Zheng, Jie J