文章：

用于解剖癌症表观基因组的化学探针工具箱

A chemical probe toolbox for dissecting the cancer epigenome

原文发布日期：2017-02-23

DOI: 10.1038/nrc.2016.148

类型: Review Article

开放获取: 否

要点：

1. Recurrent somatic mutations of genes encoding chromatin modifiers are among the most prevalent genetic events in cancer.
2. Broad epigenetic dysregulation is now understood to be a major enabling characteristic of tumour cells.
3. Validated chemical probes enable specific dissection of the molecular processes regulating gene expression at the chromatin interface.
4. By combining informative chemical probes with genetic experiments the cancer epigenome can be interrogated to identify new druggable vulnerabilities.
5. Emerging epigenetic therapies targeting DNA methylation, post-translational histone modifications and bromodomain-containing reader proteins are rapidly progressing through clinical trials and in some cases have proven efficacy in chemorefractory tumours.
6. Preclinical mechanistic data derived from chemical probes provide an important tool for deploying new epigenetically targeted drugs in rational combinations with existing therapeutics while enriching for patient disease groups who are most likely to benefit.

要点翻译：

1. 编码染色质修饰剂的基因发生体细胞重复突变是癌症中最常见的遗传事件之一。
2. 目前认为，广泛的表观遗传失调是肿瘤细胞的一个主要促成特征。
3. 经过验证的化学探针能够特异性解析染色质界面调控基因表达的分子过程。
4. 通过将信息丰富的化学探针与遗传实验相结合，可以研究癌症表观基因组，以确定新的可成药脆弱点。
5. 针对DNA甲基化、翻译后组蛋白修饰和含溴结构域阅读器蛋白的新型表观遗传疗法正在临床试验中迅速推进，并在某些情况下对化疗耐药肿瘤显示出疗效。
6. 来自化学探针的临床前机制数据为将新型表观遗传靶向药物与现有疗法合理组合提供了重要工具，同时可筛选最可能获益的患者群体。

英文摘要：

Cancer cell hallmarks are underpinned by transcriptional programmes operating in the context of a dynamic and complicit epigenomic environment. Somatic alterations of chromatin modifiers are among the most prevalent cancer perturbations. There is a pressing need for targeted chemical probes to dissect these complex, interconnected gene regulatory circuits. Validated chemical probes empower mechanistic research while providing the pharmacological proof of concept that is required to translate drug-like derivatives into therapy for cancer patients. In this Review, we describe chemical probe development for epigenomic effector proteins that are linked to cancer pathogenesis. By annotating these reagents, we aim to share our perspectives on an informative 'epigenomic toolbox' of broad utility to the research community.

摘要翻译： 

癌症细胞的特征，是在动态且协同的表观基因组环境中运行的转录程序所支撑的。染色质修饰因子的体细胞改变，是癌症中最常见的扰动之一。当前亟需靶向化学探针，以解析这些复杂且相互关联的基因调控回路。经验证的化学探针不仅能推动机制研究，还能提供药效学概念验证，为将类药衍生物转化为癌症患者的疗法奠定基础。在本综述中，我们介绍了与癌症发病机制相关的表观基因组效应蛋白的化学探针开发。通过注释这些试剂，我们旨在分享对一套具广泛研究社区价值的“表观基因组工具箱”的见解。

原文链接：

A chemical probe toolbox for dissecting the cancer epigenome