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Reversible Inhibitor of p97, DBeQ, Impairs Both Ubiquitin-Dependent and Autophagic Protein Clearance Pathways

Reversible Inhibitor of p97, DBeQ, Impairs Both Ubiquitin-Dependent and Autophagic Protein Clearance Pathways

Tsui-Fen Chou, Steve J Brown, Dmitriy Minond, Brian E Nordin, Kelin Li, Amanda C Jones, Peter Chase, Patrick R Porubsky, Brian M Stoltz, Frank J Schoenen, Matthew P Patricelli, Peter Hodder, Hugh Rosen, etc.

Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4834-9.

PMID: 21383145

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. N2,N4-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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42410914	p97 ATPase Activity Inhibitor, DBeQ			Price
IAR4242996	DBeQ			Price

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