TY - JOUR
T1 - The proteasome as a druggable target with multiple therapeutic potentialities
T2 - Cutting and non-cutting edges
AU - Tundo, G. R.
AU - Sbardella, D.
AU - Santoro, A. M.
AU - Coletta, A.
AU - Oddone, F.
AU - Grasso, G.
AU - Milardi, D.
AU - Lacal, P. M.
AU - Marini, S.
AU - Purrello, R.
AU - Graziani, G.
AU - Coletta, M.
N1 - Funding Information:
This work was supported by the Italian Ministery of University and Research (PRIN 2017SNRXH3 ), the Italian Association for Cancer Research (AIRC) under IG 2017 - ID. 20353 project-PI_Grazia Graziani, the Italian Ministry of Health RC18-2638151 to P.M.L. Special thanks are due to Omikron Italia SrL for a liberal donation.
Publisher Copyright:
© 2020 Elsevier Inc.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/9
Y1 - 2020/9
N2 - Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in the front-line setting. Thereafter, two other proteasome inhibitors (carfilzomib and ixazomib), designed to overcome resistance to bortezomib, have been approved for treatment-experienced patients, and a variety of novel inhibitors are currently under preclinical and clinical investigation not only for haematological malignancies but also for solid tumours. However, since UPS collapse leads to toxic misfolded proteins accumulation, proteasome is attracting even more interest as a target for the care of neurodegenerative diseases, which are sustained by UPS impairment. Thus, conceptually, proteasome activation represents an innovative and largely unexplored target for drug development. According to a multidisciplinary approach, spanning from chemistry, biochemistry, molecular biology to pharmacology, this review will summarize the most recent available literature regarding different aspects of proteasome biology, focusing on structure, function and regulation of proteasome in physiological and pathological processes, mostly cancer and neurodegenerative diseases, connecting biochemical features and clinical studies of proteasome targeting drugs.
AB - Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in the front-line setting. Thereafter, two other proteasome inhibitors (carfilzomib and ixazomib), designed to overcome resistance to bortezomib, have been approved for treatment-experienced patients, and a variety of novel inhibitors are currently under preclinical and clinical investigation not only for haematological malignancies but also for solid tumours. However, since UPS collapse leads to toxic misfolded proteins accumulation, proteasome is attracting even more interest as a target for the care of neurodegenerative diseases, which are sustained by UPS impairment. Thus, conceptually, proteasome activation represents an innovative and largely unexplored target for drug development. According to a multidisciplinary approach, spanning from chemistry, biochemistry, molecular biology to pharmacology, this review will summarize the most recent available literature regarding different aspects of proteasome biology, focusing on structure, function and regulation of proteasome in physiological and pathological processes, mostly cancer and neurodegenerative diseases, connecting biochemical features and clinical studies of proteasome targeting drugs.
KW - Cancer
KW - Neurodegeneration
KW - Proteasome
KW - Proteasome inhibitors
KW - SARS-Cov-2
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U2 - 10.1016/j.pharmthera.2020.107579
DO - 10.1016/j.pharmthera.2020.107579
M3 - Review article
C2 - 32442437
AN - SCOPUS:85088019708
VL - 213
JO - Pharmacology and Therapeutics
JF - Pharmacology and Therapeutics
SN - 0163-7258
M1 - 107579
ER -