Deubiquitylating enzymes and drug discovery: emerging opportunities.
Deubiquitylating enzymes and drug discovery: emerging opportunities.
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DOI：
10.1038/nrd.2017.152
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发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Jackson SP
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文献类型：
--
作者：
Harrigan JA;Jacq X;Martin NM;Jackson SP
去泛素化酶（deubiquitylating enzyme， DUB）家族包含约100种蛋白，可从多种底物中去除翻译后修饰的泛素。dub在与自身免疫性疾病、慢性炎症、肿瘤和神经变性等病理高度相关的细胞生物学的各个领域发挥着关键作用。dub是小分子药物发现的有吸引力的靶标，因为它们含有一个明确的活性位点，并且它们中的大多数具有催化半胱氨酸。活性位点半胱氨酸的氧化水解是DUB抑制剂筛选的一个挑战，因为通常需要还原剂来维持DUB活性，但如果高浓度使用，往往会导致高假阳性率。许多报道的DUB抑制剂在生化选择性分析中显示出相当非选择性。筛选底物和技术的最新进展，以及用于监测靶标参与的基于活性的探针，促进了DUB药物发现的进展。对DUB生物学的进一步了解和强效和选择性DUB抑制剂的新例子表明，DUB抑制剂的临床开发即将到来。本文的在线版本（doi:10.1038/nrd.2017.152）包含补充材料，授权用户可使用。去泛素化酶（DUBs）与多种人类疾病有关，包括癌症、神经退行性疾病、炎症和自身免疫性疾病以及传染病。在这里，Jackson及其同事讨论了DUB的病理作用，考虑了选择性DUB抑制剂开发中的挑战，并强调了即将进行临床试验的第一代药物。本文的在线版本（doi:10.1038/nrd.2017.152）包含补充材料，授权用户可使用。在因发现泛素-蛋白酶体系统以及蛋白酶体和泛素E3连接酶抑制剂获得临床批准而获得诺贝尔奖十多年后，第一代去泛素化酶（DUB）抑制剂现在正接近临床试验。然而，尽管我们对DUB的生理和病理生理作用的了解已经有了巨大的发展，但选择性DUB抑制剂的临床开发一直具有挑战性。在这篇综述中，我们讨论了这些问题，并强调了我们对DUB酶学和生物学的理解以及技术进步的最新进展，这些进展促进了目前对DUB作为从肿瘤到神经退行性疾病的治疗靶点的兴趣。本文的在线版本（doi:10.1038/nrd.2017.152）包含补充材料，授权用户可使用。
The deubiquitylating enzyme (DUB) family contains ~100 proteins that remove the post-translational modification ubiquitin from a variety of substrates. DUBs have key roles in various areas of cell biology of high relevance to pathologies such as autoimmune disorders, chronic inflammation, oncology and neurodegeneration. DUBs are attractive targets for small-molecule drug discovery, as they contain a well-defined active site, and the majority of them have a catalytic cysteine. Oxidative hydrolysis of the active-site cysteine is a challenge for DUB inhibitor screening, as reducing agents are often required to maintain DUB activity but frequently result in high false-positive rates if used at high concentrations. Many of the reported DUB inhibitors have been shown to be rather non-selective in biochemical selectivity profiling assays. Recent advances in screening substrates and technologies, as well as activity-based probes for monitoring target engagement, have facilitated progress in DUB drug discovery. Increased understanding of DUB biology and emerging examples of potent and selective DUB inhibitors suggest that clinical development of DUB inhibitors is on the horizon. The online version of this article (doi:10.1038/nrd.2017.152) contains supplementary material, which is available to authorized users. Deubiquitylating enzymes (DUBs) have been implicated in several human diseases, including cancer, neurodegenerative diseases, inflammatory and autoimmune disorders, as well as infectious diseases. Here, Jackson and colleagues discuss the pathological roles of DUBs, consider the challenges in the development of selective DUB inhibitors and highlight first-generation agents approaching clinical trials. The online version of this article (doi:10.1038/nrd.2017.152) contains supplementary material, which is available to authorized users. More than a decade after a Nobel Prize was awarded for the discovery of the ubiquitin–proteasome system and clinical approval of proteasome and ubiquitin E3 ligase inhibitors, first-generation deubiquitylating enzyme (DUB) inhibitors are now approaching clinical trials. However, although our knowledge of the physiological and pathophysiological roles of DUBs has evolved tremendously, the clinical development of selective DUB inhibitors has been challenging. In this Review, we discuss these issues and highlight recent advances in our understanding of DUB enzymology and biology as well as technological improvements that have contributed to the current interest in DUBs as therapeutic targets in diseases ranging from oncology to neurodegeneration. The online version of this article (doi:10.1038/nrd.2017.152) contains supplementary material, which is available to authorized users.
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DOI：
10.1074/jbc.m114.609644
发表时间：
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期刊：
The Journal of biological chemistry
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