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

被引:263
作者
Chou, Tsui-Fen [1 ]
Brown, Steve J. [2 ]
Minond, Dmitriy [3 ]
Nordin, Brian E. [4 ]
Li, Kelin [5 ]
Jones, Amanda C. [6 ]
Chase, Peter [3 ]
Porubsky, Patrick R. [5 ]
Stoltz, Brian M. [6 ]
Schoenen, Frank J. [5 ]
Patricelli, Matthew P. [4 ]
Hodder, Peter [3 ]
Rosen, Hugh [2 ]
Deshaies, Raymond J. [1 ,7 ]
机构
[1] CALTECH, Div Biol, Pasadena, CA 91125 USA
[2] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA
[3] Scripps Florida, Scripps Res Inst, Mol Screening Ctr, Jupiter, FL 33458 USA
[4] ActivX Biosci, La Jolla, CA 92037 USA
[5] Univ Kansas, Specialized Chem Ctr, Lawrence, KS 66047 USA
[6] CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA
[7] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA
基金
美国国家卫生研究院;
关键词
apoptosis; autophagy; unfolded protein response; AAA-ATPASE CDC48/P97; ENDOPLASMIC-RETICULUM STRESS; CANCER-CELLS; P97/VALOSIN-CONTAINING PROTEIN; SACCHAROMYCES-CEREVISIAE; PROTEASOME INHIBITION; ONCOGENE ADDICTION; MULTIPLE-MYELOMA; ER STRESS; APOPTOSIS;
D O I
10.1073/pnas.1015312108
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:4834 / 4839
页数:6
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