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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inhibition of oncogenic Wnt signaling through direct targeting of β-catenin
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Inhibition of oncogenic Wnt signaling through direct targeting of β-catenin

机译:通过直接靶向β-连环蛋白抑制致癌性Wnt信号转导

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摘要

Aberrant activation of signaling by the Wnt pathway is strongly implicated in the onset and progression of numerous types of cancer. Owing to the persistent dependence of these tumors on Wnt signaling for growth and survival, inhibition of this pathway is considered an attractive mechanism-based therapeutic approach. Oncogenic activation of Wnt signaling can ensue from a variety of distinct aberrations in the signaling pathway, but most share the common feature of causing increased cellular levels of β-catenin by interfering with its constitutive degradation. Β-Catenin serves as a central hub in Wnt signaling by engaging in crucial protein-protein interactions with both negative and positive effectors of the pathway. Direct interference with these protein-protein interactions is a biologically compelling approach toward suppression of β-catenin hyperactivity, but such interactions have proven intransigent with respect to small-molecule targeting. Hence β-catenin remains an elusive target for translational cancer therapy. Here we report the discovery of a hydrocarbon-stapled peptide that directly targets β-catenin and interferes with its ability to serve as a transcriptional coactivator for T-cell factor (TCF) proteins, the downstream transcriptional regulators of the Wnt pathway.
机译:Wnt途径异常激活信号转导与多种类型的癌症的发生和发展密切相关。由于这些肿瘤持续依赖于Wnt信号的生长和存活,因此抑制该途径被认为是一种有吸引力的基于机制的治疗方法。 Wnt信号传导的致癌激活可以通过信号传导途径中的各种异常来实现,但大多数具有共同的特征,即通过干扰β-catenin的组成型降解而引起细胞水平升高。 Ca-连环蛋白通过参与该途径的负效应和正效应物的关键蛋白质-蛋白质相互作用,充当Wnt信号传导的中心枢纽。对这些蛋白质-蛋白质相互作用的直接干扰是抑制β-连环蛋白过度活跃的生物学上令人信服的方法,但是事实证明,这种相互作用对于小分子靶向而言是不可改变的。因此,β-catenin仍然是转化性癌症治疗的目标。在这里,我们报道了直接靶向β-catenin并干扰其充当T细胞因子(TCF)蛋白(Wnt途径的下游转录调节因子)的转录共激活因子的能力的碳氢化合物固定肽的发现。

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  • 作者单位

    Departments of Stem Cell and Regenerative Biology Harvard University, Cambridge, MA 02138,Departments of Chemistry and Chemical Biology Harvard University, Cambridge, MA 02138,Chemical Genomics Centre of the Max Planck Society, 44227 Dortmund, Germany;

    Departments of Stem Cell and Regenerative Biology Harvard University, Cambridge, MA 02138,Departments of Chemistry and Chemical Biology Harvard University, Cambridge, MA 02138;

    Departments of Stem Cell and Regenerative Biology Harvard University, Cambridge, MA 02138,Departments of Chemistry and Chemical Biology Harvard University, Cambridge, MA 02138;

    Departments of Stem Cell and Regenerative Biology Harvard University, Cambridge, MA 02138,Departments of Chemistry and Chemical Biology Harvard University, Cambridge, MA 02138;

    Departments of Stem Cell and Regenerative Biology Harvard University, Cambridge, MA 02138;

    Departments of Stem Cell and Regenerative Biology Harvard University, Cambridge, MA 02138,Departments of Chemistry and Chemical Biology Harvard University, Cambridge, MA 02138,Departments of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138,Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02115;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    colorectal cancer; peptide engineering; targeted therapy;

    机译:大肠癌;肽工程;靶向治疗;

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