Inhibition of oncogenic Wnt signaling through direct targeting of β-catenin
Inhibition of oncogenic Wnt signaling through direct targeting of β-catenin
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DOI：
10.1073/pnas.1208396109
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发表时间：
2012-10-30
影响因子：
11.1
通讯作者：
Verdine, Gregory L.
中科院分区：
文献类型：
--
作者：
Grossmann, Tom N.;Yeh, Johannes T. -H.;Verdine, Gregory L.
Wnt信号通路的异常激活与许多类型癌症的发生和进展密切相关。由于这些肿瘤的生长和存活对Wnt信号传导的持续依赖性，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信号传导的致癌性激活可以由信号传导途径中的各种不同的畸变引起，但大多数都具有通过干扰其组成性降解而引起β-连环蛋白细胞水平增加的共同特征。β-连环蛋白通过参与与途径的负效应物和正效应物的关键蛋白质-蛋白质相互作用而在Wnt信号传导中充当中心枢纽。直接干扰这些蛋白质-蛋白质相互作用是抑制β-连环蛋白活性亢进的生物学上令人信服的方法，但这种相互作用已被证明与小分子靶向有关。因此，β-连环蛋白仍然是转化癌症治疗的难以捉摸的靶标。在这里，我们报告的碳氢化合物钉肽，直接靶向β-连环蛋白和干扰其作为转录辅激活因子的T细胞因子（TCF）蛋白，Wnt通路的下游转录调节因子的能力的发现。
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 beta-catenin by interfering with its constitutive degradation. beta-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 beta-catenin hyperactivity, but such interactions have proven intransigent with respect to small-molecule targeting. Hence beta-catenin remains an elusive target for translational cancer therapy. Here we report the discovery of a hydrocarbon-stapled peptide that directly targets beta-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.