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Pharmacological targets in the ubiquitin system offer new ways of treating cancer, neurodegenerative disorders and infectious diseases

  • Mariola J. Edelmann (a1), Benjamin Nicholson (a2) and Benedikt M. Kessler (a3)
Abstract

Recent advances in the development and discovery of pharmacological interventions within the ubiquitin–proteasome system (UPS) have uncovered an enormous potential for possible novel treatments of neurodegenerative disease, cancer, immunological disorder and microbial infection. Interference with proteasome activity, although initially considered unlikely to be exploitable clinically, has already proved to be very effective against haematological malignancies, and more specific derivatives that target subsets of proteasomes are emerging. Recent small-molecule screens have revealed inhibitors against ubiquitin-conjugating and -deconjugating enzymes, many of which have been evaluated for their potential use as therapeutics, either as single agents or in synergy with other drugs. Here, we discuss recent advances in the characterisation of novel UPS modulators (in particular, inhibitors of ubiquitin-conjugating and -deconjugating enzymes) and how they pave the way towards new therapeutic approaches for the treatment of proteotoxic disease, cancer and microbial infection.

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Corresponding author
*Corresponding authors: Benedikt M. Kessler, Henry Wellcome Building for Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. E-mail: bmk@ccmp.ox.ac.uk and Mariola J. Edelmann, Institute for Genomics, Biocomputing and Biotechnology, Mississippi Agricultural and Forestry, Experimental Station, Pace Seed Lab, Rm 115, Mississippi State University, 650 Stone Boulevard, Mississippi State, MS 39762, USA. E-mail: mje100@mafes.msstate.edu
References
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Eldridge, A.G. and O'Brien, T. (2010) Therapeutic strategies within the ubiquitin proteasome system. Cell Death and Differentiation 17, 4-13
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