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Abstract
<p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="first" id="d13152875e71">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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