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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Chou, Tsui-fen Stoltz, Brian M. Minond, Dmitriy Li, Kelin Deshaies, Raymond J. Nordin, Brian E. Hodder, Peter Rosen, Hugh Chase, Peter Schoenen, Frank J. Porubsky, Patrick R. Patricelli, Matthew P. Brown, Steve J. Jones, Amanda C. |
| Description | Author Affiliation: Chou TF ( Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA. tfchou@caltech.edu); |
| Abstract | A specific small-molecule inhibitor of p97 would provide an important tool to investigate diverse functions of this essential ATPase associated with diverse cellular activities (AAA) ATPase and to evaluate its potential to be a therapeutic target in human disease. We carried out a high-throughput screen to identify inhibitors of p97 ATPase activity. Dual-reporter cell lines that simultaneously express p97-dependent and p97-independent proteasome substrates were used to stratify inhibitors that emerged from the screen. N2,N4-dibenzylquinazoline-2,4-diamine (DBeQ) was identified as a selective, potent, reversible, and ATP-competitive p97 inhibitor. DBeQ blocks multiple processes that have been shown by RNAi to depend on p97, including degradation of ubiquitin fusion degradation and endoplasmic reticulum-associated degradation pathway reporters, as well as autophagosome maturation. DBeQ also potently inhibits cancer cell growth and is more rapid than a proteasome inhibitor at mobilizing the executioner caspases-3 and -7. Our results provide a rationale for targeting p97 in cancer therapy. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 12 |
| Volume Number | 108 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2011-03-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Adenosine Triphosphatases Antagonists & Inhibitors Metabolism Autophagy Drug Effects Endoplasmic Reticulum Enzymology Enzyme Inhibitors Pharmacology Nuclear Proteins Quinazolines Ubiquitin Genetics Animals Antineoplastic Agents Chemical Synthesis Chemistry Caspase 3 Caspase 7 Cell Line Mice Neoplasms Drug Therapy Proteasome Endopeptidase Complex Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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