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.
Keywords: Inhibitors, proteasome, cancer, ubiquitin, SUMO, NEDD8, conjugating enzymes, ligases, isopeptidases, bortezomib.
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