The therapeutic potential of deubiquitinating enzyme inhibitors
The therapeutic potential of deubiquitinating enzyme inhibitors
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DOI：
10.1042/bst0380137
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发表时间：
2010-02-01
影响因子：
3.9
通讯作者：
Colland, Frederic
中科院分区：
文献类型：
--
作者：
Colland, Frederic
蛋白酶在各种病理过程中发挥着关键作用，并且已经有几种蛋白酶抑制剂可用于治疗。DUBs（去泛素化酶）是人类蛋白酶中最大的一类，是泛素-蛋白酶体系统的关键效应子。这种调节细胞蛋白质周转的途径与许多人类疾病的发病机制有关，包括神经退行性疾病、病毒性疾病和癌症。蛋白酶体抑制剂Velcade（R）（硼替佐米）治疗多发性骨髓瘤和套细胞淋巴瘤的疗效确立了该系统作为癌症治疗的有效靶点。靶向蛋白酶体本身的一个有希望的替代方案是靶向上游的泛素缀合/去缀合系统，以产生更特异、毒性更低的抗癌剂。本文综述了近年来特异性靶向DUBs的小分子抑制剂的研究进展。
Proteases play a key role in various pathological processes and several protease inhibitors are already available for treatment. DUBs (deubiquitinating enzymes) constitute one of the largest classes of human proteases and are key effectors of the ubiquitin-proteasome system. This pathway regulating cellular protein turnover has been implicated in the pathogenesis of many human diseases, including neurodegenerative disorders, viral diseases and cancer. The therapeutic efficacy of the proteasome inhibitor Velcade (R) (bortezomib) for treating multiple myeloma and mantle cell lymphoma establishes this system as a valid target for cancer treatment. A promising alternative to targeting the proteasome itself would be to target the upstream, ubiquitin conjugation/deconjugation system, to generate more specific, less toxic anticancer agents. Advances in small molecule-based inhibitors specifically targeting DUBs are presented in this review.