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

2015; Cell Press; Volume: 28; Issue: 5 Linguagem: Inglês

10.1016/j.ccell.2015.10.002

1878-3686

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 K. Shawver, Han-Jie Zhou, David J. Wustrow, Mark Rolfe,

Phagocytosis and Immune Regulation

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.