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Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis
- Anderson, Daniel J;
- Le Moigne, Ronan;
- Djakovic, Stevan;
- Kumar, Brajesh;
- Rice, Julie;
- Wong, Steve;
- Wang, Jinhai;
- Yao, Bing;
- Valle, Eduardo;
- von Soly, Szerenke Kiss;
- Madriaga, Antonett;
- Soriano, Ferdie;
- Menon, Mary-Kamala;
- Wu, Zhi Yong;
- Kampmann, Martin;
- Chen, Yuwen;
- Weissman, Jonathan S;
- Aftab, Blake T;
- Yakes, F Michael;
- Shawver, Laura;
- Zhou, Han-Jie;
- Wustrow, David;
- Rolfe, Mark
Published Web Location
https://doi.org/10.1016/j.ccell.2015.10.002Abstract
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.
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