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

by Selleckchem | Jul 17 2023

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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Protein homeostasis, or the balance between protein synthesis and degradation, is crucial for maintaining proper cellular function. Deficiencies in protein homeostasis have been implicated in various diseases, including cancer and neurodegenerative disorders. The two main pathways responsible for protein degradation in mammalian cells are the ubiquitin-proteasome system (UPS) and autophagy.

The UPS involves tagging proteins with ubiquitin molecules, which target them for degradation by the proteasome. Autophagy, on the other hand, involves the formation of autophagosomes that engulf and deliver proteins and other cellular components to lysosomes for degradation. Given the significance of these pathways in maintaining protein homeostasis, they have emerged as attractive targets for therapeutic interventions in cancer and neurodegenerative diseases.

One central component of the UPS is the ATPase p97, also known as VCP (valosin-containing protein). p97 plays a crucial role in protein degradation by extracting and disassembling its substrates from various cellular locations. Additionally, p97 is involved in regulating different steps of autophagy. Its critical functions in protein degradation and cellular maintenance make p97 an appealing target for drug development.

In recent years, several p97 inhibitors have been developed and tested in preclinical and clinical studies. Notably, two ATPase inhibitors, CB-5083 and CB-5339, have shown effective anti-tumor activity across various tumor models and have progressed to clinical trials. These inhibitors provide a promising alternative for targeting protein degradation in cancer therapy.

The evolution of p97 inhibitors has involved their initial development as research tools to investigate the functions of p97 in cellular processes. However, their potential as therapeutic agents has been recognized, leading to the design and optimization of inhibitors with improved drug-like properties for clinical use. The development of p97 inhibitors has been guided by the understanding of the protein's structure and mechanism of action, as well as the identification of specific disease contexts where targeting p97 may be beneficial.

In summary, the development of p97 inhibitors represents a significant advancement in the field of protein degradation and offers potential therapeutic options for cancer and neurodegenerative diseases. Further research and clinical trials will help to determine the efficacy and safety of these inhibitors, and their successful development may open new avenues for targeted therapies in the future.