Emerging Potential of Therapeutic Targeting of Ubiquitin-Specific Proteases in the Treatment of Cancer

被引:168
作者
Pal, Anupama [1 ]
Young, Matthew A. [2 ]
Donato, Nicholas J. [3 ,4 ]
机构
[1] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Sch Med, Div Hematol Oncol, Dept Internal Med, Ann Arbor, MI 48109 USA
[4] Ctr Comprehens Canc, Ann Arbor, MI USA
关键词
NF-KAPPA-B; DEUBIQUITINATING ENZYME USP17; SMALL-MOLECULE INHIBITOR; STRUCTURAL BASIS; DEUBIQUITYLATING ENZYME; MULTIPLE-MYELOMA; CATALYTIC DOMAIN; OVER-EXPRESSION; BINDING DOMAIN; P53;
D O I
10.1158/0008-5472.CAN-14-1211
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The ubiquitin-proteasome system (UPS) has emerged as a therapeutic focus and target for the treatment of cancer. The most clinically successful UPS-active agents (bortezomib and lenalidomide) are limited in application to hematologic malignancies, with only marginal efficacy in solid tumors. Inhibition of specific ubiquitin E3 ligases has also emerged as a valid therapeutic strategy, and many targets are currently being investigated. Another emerging and promising approach in regulation of the UPS involves targeting deubiquitinases (DUB). The DUBs comprise a relatively small group of proteins, most with cysteine protease activity that target several key proteins involved in regulation of tumorigenesis, apoptosis, senescence, and autophagy. Through their multiple contacts with ubiquitinated protein substrates involved in these pathways, DUBs provide an untapped means of modulating many important regulatory proteins that support oncogenic transformation and progression. Ubiquitin-specific proteases (USP) are one class of DUBs that have drawn special attention as cancer targets, as many are differentially expressed or activated in tumors or their microenvironment, making them ideal candidates for drug development. This review attempts to summarize the USPs implicated in different cancers, the current status of USP inhibitor-mediated pharmacologic intervention, and future prospects for USP inhibitors to treat diverse cancers. (C)2014 AACR.
引用
收藏
页码:4955 / 4966
页数:12
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