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Development of p97 AAA ATPase inhibitors

Chou, Tsui-Fen and Deshaies, Raymond J. (2011) Development of p97 AAA ATPase inhibitors. Autophagy, 7 (9). pp. 1091-1092. ISSN 1554-8627. PMCID PMC3210319. doi:10.4161/auto.7.9.16489.

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Specific p97 inhibitors are valuable research tools to carry out mechanistic and cellular investigations of p97 biology. p97 is an abundant, ubiquitin-selective chaperone that has multiple functions and is essential for life. Therefore, genetic methods that require long incubations like siRNA or expression of dominant-negative p97 mutants are likely to generate complicated outcomes due to secondary consequences that arise upon slow depletion of p97 activity. We recently identified a small molecule p97 inhibitor, N^2,N^4-dibenzylquinazoline-2,4-diamine (DBeQ), and documented its effects on blocking autophagic degradation of LC3-II and proteasomal degradation of a p97-dependent ubiquitin-proteasome system (UPS) substrate. What distinguishes DBeQ from conventional proteasome inhibitors is that DBeQ affects both the UPS and autophagic protein degradation pathways and rapidly activates cell death. Whether DBeQ activates autophagic and/or apoptotic cell death will require further work to evaluate its detailed mechanism of action. An exciting goal for the future will be to generate p97 inhibitors that affect one or the other pathway. We propose that generation of 'separation of function' inhibitors will be a challenging adventure for chemical biologists but will yield extremely powerful tools to study p97 and enable evaluation of the therapeutic potential of targeting distinct p97 complexes.

Item Type:Article
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URLURL TypeDescription CentralArticle
Chou, Tsui-Fen0000-0003-2410-2186
Deshaies, Raymond J.0000-0002-3671-9354
Additional Information:© 2011 Landes Bioscience. Submitted: 04-28-11. Revised: 05-03-11. Accepted: 05-13-11. We thank H. Park, R. Oania and D. Shimoda for technical assistance. 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 a National Institutes of Health R03 grant (MH085687).
Funding AgencyGrant Number
Multiple Myeloma Research FoundationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Weston Havens FoundationUNSPECIFIED
NIHR03 MH085687
Subject Keywords:p97/VCP, chemical inhibitor, caspase, high-throughput screening, cancer therapeutic, DBeQ, autophagy, ERAD
Issue or Number:9
PubMed Central ID:PMC3210319
Record Number:CaltechAUTHORS:20110930-072701050
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Official Citation:Chou TF, Deshaies RJ. Development of p97 AAA ATPase inhibitors. Autophagy. 2011 Sep 1;7(9):1091-2. Epub 2011 Sep 1. PubMed PMID: 21606684.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:25504
Deposited By: Ruth Sustaita
Deposited On:30 Sep 2011 16:37
Last Modified:09 Nov 2021 16:34

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