Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 12, Pages 4834-4839Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1015312108
Keywords
apoptosis; autophagy; unfolded protein response
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Funding
- National Institutes of Health (NIH) [MH074404]
- National Human Genome Research Institute [U54 HG005031-02]
- NIH [F32GM082000, R03 Grant MH085687]
- Multiple Myeloma Research Foundation
- Howard Hughes Medical Institute (HHMI)
- Weston Havens Foundation
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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. N(2), N(4)-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.
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