A useful approach to identify novel small-molecule inhibitors of Wnt-dependent transcription.
A useful approach to identify novel small-molecule inhibitors of Wnt-dependent transcription.
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DOI：
10.1158/0008-5472.can-10-1028
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发表时间：
2010-07-15
期刊：
影响因子：
11.2
通讯作者：
Dale T
中科院分区：
文献类型：
--
作者：
Ewan K;Pajak B;Stubbs M;Todd H;Barbeau O;Quevedo C;Botfield H;Young R;Ruddle R;Samuel L;Battersby A;Raynaud F;Allen N;Wilson S;Latinkic B;Workman P;McDonald E;Blagg J;Aherne W;Dale T
由于编码APC、β-catenin和轴蛋白的基因突变，Wnt信号通路在癌症中经常被解除调控。为了确定Wnt信号传导的小分子抑制剂作为潜在的治疗药物，使用tcf报告细胞系筛选了多种化学文库，其中该途径的活性在Disheveled蛋白水平上被诱导。通过一系列的反卷积研究，我们重点研究了3个化合物系列，它们选择性地杀死了具有组成型Wnt信号的癌细胞系。这些化合物的活性包括诱导被GSK-3抑制剂稳定的β-catenin降解的能力。该筛选说明了一种确定Wnt信号小分子抑制剂的实用方法，可以为开发适合治疗Wnt依赖性肿瘤患者的药物提供种子。
The Wnt signaling pathway is frequently deregulated in cancer due to mutations in the genes encoding APC, β-catenin and axin. To identify small molecule inhibitors of Wnt signaling as potential therapeutics, a diverse chemical library was screened using a TCF-reporter cell line in which the activity of the pathway was induced at the level of the Disheveled protein. A series of deconvolution studies was used to focus on 3 compound series that selectively killed cancer cell lines with constitutive Wnt signaling. Activities of the compounds included the ability to induce degradation of β-catenin that had been stabilized by a GSK-3 inhibitor. This screen illustrates a practical approach to identify small molecule inhibitors of Wnt signaling that can seed the development of agents suitable to treat patients with Wnt-dependent tumors.