title: Selective inhibitor of proteasome's caspase-like sites sensitizes cells to specific inhibition of chymotrypsin-like sites.
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.
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, 1 Medical Center Drive, HB7936, Lebanon, NH 03756, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Britton
authors.forename: Marcella M
authors.initials: MM
authors.lastname: Lucas
authors.forename: Sondra L
authors.initials: SL
authors.lastname: Downey
authors.forename: Michael
authors.initials: M
authors.lastname: Screen
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Pletnev
authors.forename: Martijn
authors.initials: M
authors.lastname: Verdoes
authors.forename: Robert A
authors.initials: RA
authors.lastname: Tokhunts
authors.forename: Omar
authors.initials: O
authors.lastname: Amir
authors.forename: Ayrton L
authors.initials: AL
authors.lastname: Goddard
authors.forename: Philip M
authors.initials: PM
authors.lastname: Pelphrey
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Wright
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.forename: Alexei F
authors.initials: AF
authors.lastname: Kisselev
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D020169:Caspases / Q000378:metabolism; D020134:Catalytic Domain; D002460:Cell Line; D002918:Chymotrypsin / Q000378:metabolism; D006801:Humans; D011480:Protease Inhibitors / Q000737:chemistry* / Q000633:toxicity; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D002918:Chymotrypsin; D020169:Caspases; D046988:Proteasome Endopeptidase Complex