Drugging the undruggables： exploring the ubiquitin system for drug development

Dynamic modulation of protein levels is tightly controlled in response to physiological cues. In mammalian cells, much of the protein degradation is carried out by the ubiquitin-proteasome system （UPS）. Similar to kinases, com- ponents of the ubiquitin system are often dysregulated, leading to a var...

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Bibliographic Details
Published in:	Cell research Vol. 26; no. 4; pp. 484 - 498
Main Authors:	Huang, Xiaodong, Dixit, Vishva M
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-04-2016 Nature Publishing Group
Subjects:	631/45/612/645 631/67/1059 631/80/458/582 692/308/153 Biodegradation Biomedical and Life Sciences Cell Biology Drug Discovery Life Sciences Proteasome Endopeptidase Complex - metabolism Proteasome Inhibitors Review Ubiquitin - metabolism Ubiquitination - drug effects 动态调制哺乳动物细胞泛素-蛋白酶体系统美国食品药物开发药物靶点蛋白质水平蛋白质降解 hydrophobic tag ubiquitin-proteasome system SERD PROTAC drug target degrader
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Summary:	Dynamic modulation of protein levels is tightly controlled in response to physiological cues. In mammalian cells, much of the protein degradation is carried out by the ubiquitin-proteasome system （UPS）. Similar to kinases, com- ponents of the ubiquitin system are often dysregulated, leading to a variety of diseases, including cancer and neuro- degeneration, making them attractive drug targets. However, so far there are only a handful of drugs targeting the ubiquitin system that have been approved by the FDA. Here, we review possible therapeutic intervention nodes in the ubiquitin system, analyze the challenges, and highlight the most promising strategoies to targoet the UPS.
Bibliography:	Dynamic modulation of protein levels is tightly controlled in response to physiological cues. In mammalian cells, much of the protein degradation is carried out by the ubiquitin-proteasome system （UPS）. Similar to kinases, com- ponents of the ubiquitin system are often dysregulated, leading to a variety of diseases, including cancer and neuro- degeneration, making them attractive drug targets. However, so far there are only a handful of drugs targeting the ubiquitin system that have been approved by the FDA. Here, we review possible therapeutic intervention nodes in the ubiquitin system, analyze the challenges, and highlight the most promising strategoies to targoet the UPS. 31-1568 ubiquitin-proteasome system; drug target; degrader; PROTAC; hydrophobic tag; SERD ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-3 content type line 23 ObjectType-Review-1
ISSN:	1001-0602 1748-7838
DOI:	10.1038/cr.2016.31