Inhibitors of the ATPase p97/VCP: From basic research to clinical applications

Protein homeostasis deficiencies underlie various cancers and neurodegenerative diseases. The ubiquitin-proteasome system (UPS) and autophagy are responsible for most of the protein degradation in mammalian cells and, therefore, represent attractive targets for cancer therapy and that of neurodegene...

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Bibliographic Details
Published in:Cell chemical biology Vol. 30; no. 1; p. 3
Main Authors: Kilgas, Susan, Ramadan, Kristijan
Format: Journal Article
Language:English
Published: United States 19.01.2023
Subjects:
Adenosine Triphosphatases - metabolism
Animals
Cell Cycle Proteins - metabolism
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - therapeutic use
Humans
Mammals - metabolism
Neoplasms - drug therapy
Ubiquitin - metabolism
Valosin Containing Protein - metabolism
CB-5083
antimicrobial
cancer therapy
p97 inhibitors
CB-5339
anti-inflammatory
p97/VCP
ISSN:2451-9448, 2451-9448
Online Access:Get more information
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Summary:Protein homeostasis deficiencies underlie various cancers and neurodegenerative diseases. The ubiquitin-proteasome system (UPS) and autophagy are responsible for most of the protein degradation in mammalian cells and, therefore, represent attractive targets for cancer therapy and that of neurodegenerative diseases. The ATPase p97, also known as VCP, is a central component of the UPS that extracts and disassembles its substrates from various cellular locations and also regulates different steps in autophagy. Several UPS- and autophagy-targeting drugs are in clinical trials. In this review, we focus on the development of various p97 inhibitors, including the ATPase inhibitors CB-5083 and CB-5339, which reached clinical trials by demonstrating effective anti-tumor activity across various tumor models, providing an effective alternative to targeting protein degradation for cancer therapy. Here, we provide an overview of how different p97 inhibitors have evolved over time both as basic research tools and effective UPS-targeting cancer therapies in the clinic.
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ISSN:2451-9448
2451-9448
DOI:10.1016/j.chembiol.2022.12.007