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Chem Biol. 2009 Dec 24;16(12):1278-89. doi: 10.1016/j.chembiol.2009.11.015.

Selective inhibitor of proteasome's caspase-like sites sensitizes cells to specific inhibition of chymotrypsin-like sites.

Author information

1
Department of Pharmacology and Toxicology, Dartmouth Medical School, 1 Medical Center Drive, HB7936, Lebanon, NH 03756, USA.

Abstract

Proteasomes degrade most proteins in mammalian cells and are established targets of anticancer drugs. All eukaryotic proteasomes have three types of active sites: chymotrypsin-like, trypsin-like, and caspase-like. Chymotrypsin-like sites are the most important in protein degradation and are the primary target of most proteasome inhibitors. The biological roles of trypsin-like and caspase-like sites and their potential as cotargets of antineoplastic agents are not well defined. Here we describe the development of site-specific inhibitors and active-site probes of chymotrypsin-like and caspase-like sites. Using these compounds, we show that cytotoxicity of proteasome inhibitors does not correlate with inhibition of chymotrypsin-like sites and that coinhibition of either trypsin-like and/or caspase-like sites is needed to achieve maximal cytotoxicity. Thus, caspase-like and trypsin-like sites must be considered as cotargets of anticancer drugs.

PMID:
20064438
PMCID:
PMC2807417
DOI:
10.1016/j.chembiol.2009.11.015
[Indexed for MEDLINE]
Free PMC Article

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