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Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways

Chou, Tsui-Fen and Brown, Steve J. and Minond, Dmitriy and Nordin, Brian E. and Li, Kelin and Jones, Amanda C. and Chase, Peter and Porubsky, Patrick R. and Stoltz, Brian M. and Schoenen, Frank J. and Patricelli, Matthew P. and Hodder, Peter and Rosen, Hugh and Deshaies, Raymond J. (2011) Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways. Proceedings of the National Academy of Sciences of the United States of America, 108 (12). pp. 4834-4839. ISSN 0027-8424. PMCID PMC3064330. https://resolver.caltech.edu/CaltechAUTHORS:20110414-085357247

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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. 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1015312108DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064330/PubMed CentralArticle
ORCID:
AuthorORCID
Chou, Tsui-Fen0000-0003-2410-2186
Jones, Amanda C.0000-0001-8426-8407
Stoltz, Brian M.0000-0001-9837-1528
Deshaies, Raymond J.0000-0002-3671-9354
Additional Information:© 2011 National Academy of Sciences. Edited by Randy King, Harvard University, Cambridge, MA, and accepted by the Editorial Board February 4, 2011 (received for review October 12, 2010). Published online before print March 7, 2011. We thank A. Brunger for providing plasmids; G. Georg for a useful suggestion regarding high-throughput screen validation; C. Weihl for helpful discussions; P. Baillargeon and L. DeLuca for compound management; F. Parlati for critical reading of the manuscript; and H. Park, R. Oania, and D. Shimoda for technical assistance. National Institutes of Health (NIH) U54 Grant MH074404 funded Scripps personnel. The University of Kansas was supported by Award U54 HG005031-02 administered by the National Human Genome Research Institute on behalf of the NIH Roadmap Molecular Libraries Program. A.C.J. was supported by NIH Grant F32GM082000. T.-F.C. was supported by a 2008 Fellows Grant Program Award from the Multiple Myeloma Research Foundation, the Howard Hughes Medical Institute (HHMI), and the Weston Havens Foundation. R.J.D. is an HHMI Investigator, and this work was funded in part by HHMI and in part by NIH R03 Grant MH085687. Author contributions: T.-F.C., B.M.S., F.J.S., M.P.P., P.H., H.R., and R.J.D. designed research; T.-F.C., S.J.B., D.M., B.E.N., K.L., A.C.J., P.C., and P.R.P. performed research; T.-F.C. and R.J.D. analyzed data; and T.-F.C. and R.J.D. wrote the paper.
Funders:
Funding AgencyGrant Number
NIHU54 MH074404
NIHU54 HG005031-02
NIH Postdoctoral FellowshipF32GM082000
Multiple Myeloma Research FoundationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Weston Havens FoundationUNSPECIFIED
NIHR03 MH085687
National Human Genome Research InstituteUNSPECIFIED
Subject Keywords:apoptosis; autophagy; unfolded protein response
Issue or Number:12
PubMed Central ID:PMC3064330
Record Number:CaltechAUTHORS:20110414-085357247
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20110414-085357247
Official Citation:Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways PNAS 2011 108 (12) 4834-4839; published ahead of print March 7, 2011, doi:10.1073/pnas.1015312108
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:23315
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:14 Apr 2011 18:13
Last Modified:27 Apr 2020 22:03

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