The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole blocks nuclear factor-kappaB activation through direct inhibition of IkappaB kinase beta.
The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) is a multifunctional agent with potent anti-inflammatory, antiproliferative, cytoprotective, and apoptotic activities, whose molecular targets are unknown. Using both cell-free and cellular assays, we show that CDDO-Im is a direct inhibitor of IkappaB kinase (IKK) beta and that it thereby inhibits binding of nuclear factor-kappaB to DNA and subsequent transcriptional activation. Pretreatment of cells with CDDO-Im prevents IkappaBalpha phosphorylation and degradation in response to tumor necrosis factor alpha. The kinetics of this inhibition by CDDO-Im are rapid and occur within 15 min. A biotinylated analogue of CDDO-Im showed that CDDO-Im binds to the IKK signalsome. Furthermore, we show that Cys(179) on IKK is a target for CDDO-Im. This is the first report to show that this novel synthetic triterpenoid binds to and inhibits IKKbeta directly.
Yore
Mark M
MM
Department of Pharmacology, Dartmouth Medical School, Hanover, NH 03755, USA.
Liby
Karen T
KT
Honda
Tadashi
T
Gribble
Gordon W
GW
Sporn
Michael B
MB
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D045744:Cell Line, Tumor; D003545:Cysteine / Q000737:chemistry; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000737:chemistry
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D007093:Imidazoles; D016328:NF-kappa B; D013438:Sulfhydryl Compounds; D009828:Oleanolic Acid; D051550:I-kappa B Kinase; D003545:Cysteine