| Literature DB >> 26555175 |
Daniel J Anderson1, Ronan Le Moigne2, Stevan Djakovic2, Brajesh Kumar2, Julie Rice2, Steve Wong2, Jinhai Wang2, Bing Yao2, Eduardo Valle2, Szerenke Kiss von Soly2, Antonett Madriaga2, Ferdie Soriano2, Mary-Kamala Menon2, Zhi Yong Wu2, Martin Kampmann3, Yuwen Chen3, Jonathan S Weissman3, Blake T Aftab4, F Michael Yakes2, Laura Shawver2, Han-Jie Zhou2, David Wustrow2, Mark Rolfe2.
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.Entities:
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Year: 2015 PMID： 26555175 PMCID： PMC4941640 DOI： 10.1016/j.ccell.2015.10.002
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743