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Published February 5, 2020 | Published
Journal Article Open

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Abstract

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.

Additional Information

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Received: 12 December 2019; Accepted: 28 January 2020; Published: 5 February 2020. We thank Rusty Lipford, Rati Verma, Weiru Wang, and Ingrid Wertz for their critical reading and comments on the manuscript. We thank Ray Deshaies for introducing us to the field of ubiquitin biology. Author Contributions: D.J.S. and J.L. conceptualized, drafted and revised the manuscript. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest: D.J.S. is an employee of Amgen Inc and may hold Amgen stock.; J.L. is an employee Genentech, a member of the Roche group, and may hold Roche stock or stock options.

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