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Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways
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Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways
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Journal Article
Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways
2011
Overview
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-ḏiḇe̱nzylq̱uinazoline-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.
Publisher
National Academy of Sciences,National Acad Sciences
Subject
/ Adenosine Triphosphatases - antagonists & inhibitors
/ Adenosine Triphosphatases - genetics
/ Adenosine Triphosphatases - metabolism
/ Animals
/ Antineoplastic Agents - chemical synthesis
/ Antineoplastic Agents - chemistry
/ Antineoplastic Agents - pharmacology
/ Cancer
/ Endoplasmic Reticulum - enzymology
/ Endoplasmic Reticulum - genetics
/ Enzyme Inhibitors - chemical synthesis
/ Enzyme Inhibitors - chemistry
/ Enzyme Inhibitors - pharmacology
/ Humans
/ Mice
/ Nuclear Proteins - antagonists & inhibitors
/ Nuclear Proteins - metabolism
/ proteasome endopeptidase complex
/ Proteasome Endopeptidase Complex - genetics
/ Proteasome Endopeptidase Complex - metabolism
/ Proteins
/ Quinazolines - chemical synthesis
/ RNA
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