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Proteasome Activation to Combat Proteotoxicity
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Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

by 1,2 and 3,*
1
Amgen Research, Amgen Inc., Thousand Oaks, CA 91320, USA
2
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
3
Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(3), 671; https://doi.org/10.3390/molecules25030671
Received: 12 December 2019 / Revised: 25 January 2020 / Accepted: 28 January 2020 / Published: 5 February 2020
(This article belongs to the Special Issue Proteasome Regulators: Activators and Inhibitors)
The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome prevents the accumulation of misfolded proteins, controls the cell cycle, and regulates the immune response, to name a few important roles for this macromolecular “machine.” As a therapeutic target, proteasome inhibitors have been approved for the treatment of multiple myeloma and mantle cell lymphoma. However, inability to sufficiently inhibit proteasome activity at tolerated doses has hampered efforts to expand the scope of proteasome inhibitor-based therapies. With emerging new modalities in myeloma, it might seem challenging to develop additional proteasome-based therapies. However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases. View Full-Text
Keywords: proteostasis; proteasome; ubiquitin; immunoproteasome; unfolded protein response; Rpn11; Rpn13; p97; bortezomib; carfilzomib; ixazomib; oprozomib; marizomib; KZR-616; capzimin; RA190; RA183; KDT-11; RIP-1; NFE2L1/Nrf1 proteostasis; proteasome; ubiquitin; immunoproteasome; unfolded protein response; Rpn11; Rpn13; p97; bortezomib; carfilzomib; ixazomib; oprozomib; marizomib; KZR-616; capzimin; RA190; RA183; KDT-11; RIP-1; NFE2L1/Nrf1
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Sherman, D.J.; Li, J. Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease. Molecules 2020, 25, 671.

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