Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis.

Abstract

p97 is a AAA-ATPase with multiple cellular functions, one of which is critical regulation of protein homeostasis pathways. We describe the characterization of CB-5083, a potent, selective, and orally bioavailable inhibitor of p97. Treatment of tumor cells with CB-5083 leads to accumulation of poly-ubiquitinated proteins, retention of endoplasmic reticulum-associated degradation (ERAD) substrates, and generation of irresolvable proteotoxic stress, leading to activation of the apoptotic arm of the unfolded protein response. In xenograft models, CB-5083 causes modulation of key p97-related pathways, induces apoptosis, and has antitumor activity in a broad range of both hematological and solid tumor models. Molecular determinants of CB-5083 activity include expression of genes in the ERAD pathway, providing a potential strategy for patient selection.

• Authors: Daniel J Anderson, Ronan Le Moigne, Stevan Djakovic, Brajesh Kumar, Julie Rice, Steve Wong, Jinhai Wang, Bing Yao, Eduardo Valle, Szerenke Kiss von Soly, Antonett Madriaga, Ferdie Soriano, Mary-Kamala Menon, Zhi Yong Wu, Martin Kampmann, Yuwen Chen, Jonathan S Weissman, Blake T Aftab, F Michael Yakes, Laura Shawver, Han-Jie Zhou, David Wustrow, Mark Rolfe
• Journal: Cancer cell (Cancer Cell) Vol. 28 Issue 5 Pg. 653-665 (Nov 09 2015) ISSN: 1878-3686 [Electronic] United States
• PMID: 26555175 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• CB-5083
• Enzyme Inhibitors
• Indoles
• Nuclear Proteins
• Pyrimidines
• Ubiquitinated Proteins
• Adenosine Triphosphatases
• p97 ATPase

Topics

• Adenosine Triphosphatases (antagonists & inhibitors, genetics, metabolism)
• Animals
• Apoptosis (drug effects)
• Blotting, Western
• CRISPR-Cas Systems
• Cell Line, Tumor
• Endoplasmic Reticulum-Associated Degradation (drug effects)
• Enzyme Inhibitors (chemistry, pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• HCT116 Cells
• HEK293 Cells
• Homeostasis (drug effects)
• Humans
• Indoles (chemistry, pharmacology)
• K562 Cells
• Mice, Nude
• Mice, SCID
• Molecular Structure
• Molecular Targeted Therapy (methods)
• Neoplasms (drug therapy, genetics, metabolism)
• Nuclear Proteins (antagonists & inhibitors, genetics, metabolism)
• Pyrimidines (chemistry, pharmacology)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Ubiquitinated Proteins (metabolism)
• Xenograft Model Antitumor Assays