4.5 Article

Targeting the Ubiquitin Proteasome System: Beyond Proteasome Inhibition

期刊

CURRENT PHARMACEUTICAL DESIGN
卷 19, 期 22, 页码 4053-4093

出版社

BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1381612811319220014

关键词

Inhibitors; proteasome; cancer; ubiquitin; SUMO; NEDD8; conjugating enzymes; ligases; isopeptidases; bortezomib

资金

  1. Basque Country Government
  2. Diputacion Foral de Guip zcoa
  3. Ministerio de Economia y Competitividad [BFU2008-01108/BMC, BFU2011-28536, SAF 2011/29326]
  4. Fondo de Investigacion Sanitaria [PI09/0060]
  5. Obra Social KUTXA

向作者/读者索取更多资源

The Ubiquitin-Proteasome System (UPS) has been considered as privileged pharmacological target for drug development due to the tremendous potential for intervention on multiple pathologies including cancer, neurodegenerative diseases, immune diseases and multiple infections. The pharmacological potential of the UPS was revealed after the unpredicted success of proteasome inhibitors for the treatment of some haematological malignancies. After a decade of clinical use of bortezomib, this review summarizes part of the learned experience and recent advances on the development of alternative inhibitors of the UPS. A new generation of inhibitors, including those targeting subsets of proteasomes, are under investigation and it is likely that some of them will reach clinical trials. Beyond the proteasome inhibition, there are also other targets that can be blocked to attain directly or indirectly the UPS system. The ubiquitylation status of protein substrates is intimately linked to other post-translational modifications of the ubiquitin family, increasing the number of potential targets for clinical intervention. In addition to the obvious subsets of ubiquitin-conjugating and de-conjugating enzymes, a group of enzymatic activities regulating SUMOylation or NEDDylation have a potential impact on the activity of the UPS. The novel strategies explore the active site of those enzymes and/or the target recognition surfaces. The first inhibitors of these parallel pathways appeared to tackle a limited number of protein targets playing important roles on diverse pathologies. Although, a large majority of them have not yet been tested in clinical trials, the new inhibitors are expected to have fewer side effects than proteasome inhibitors.

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