Source:http://linkedlifedata.com/resource/pubmed/id/10076530
Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
9
|
| pubmed:dateCreated |
1999-3-30
|
| pubmed:abstractText |
The multicatalytic proteinase or proteasome is a highly conserved cellular structure that is responsible for the ATP-dependent proteolysis of many proteins involved in important regulatory cellular processes. We have identified a novel class of inhibitors of the chymotrypsin-like proteolytic activity of the 20S proteasome that exhibit IC50 values ranging from 0.1 to 0.5 microgram/mL (0.1 to 1 microM). In cell proliferation assays, these compounds inhibit growth with an IC50 ranging from 5 to 10 micrograms/mL (10-20 microM). A representative member of this class of inhibitors was tested in other biological assays. CVT-634 (5-methoxy-1-indanone-3-acetyl-leu-D-leu-1-indanylamide) prevented lipopolysaccharide (LPS), tumor necrosis factor (TNF)-, and phorbol ester-induced activation of nuclear factor kappa B (NF-kappa B) in vitro by preventing signal-induced degradation of I kappa B-alpha. In these studies, the I kappa B-alpha that accumulated was hyperphosphorylated, indicating that CVT-634 did not inhibit I kappa B-alpha kinase, the enzyme responsible for signal-induced phosphorylation of I kappa B-alpha. In vivo studies indicated that CVT-634 prevented LPS-induced TNF synthesis in a murine macrophage cell line. In addition, in mice pretreated with CVT-634 at 25 and 50 mg/kg and subsequently treated with LPS, serum TNF levels were significantly lower (225 +/- 59 and 83 +/- 41 pg/mL, respectively) than in those mice that were treated only with LPS (865 +/- 282 pg/mL). These studies suggest that specific inhibition of the chymotrypsin-like activity of the proteasome is sufficient to prevent signal-induced NF-kappa B activation and that the proteasome is a novel target for the identification of agents that may be useful in the treatment of diseases whose etiology is dependent upon the activation of NF-kappa B.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine Triphosphatases,
http://linkedlifedata.com/resource/pubmed/chemical/Calpain,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Proteinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Dipeptides,
http://linkedlifedata.com/resource/pubmed/chemical/Lipopolysaccharides,
http://linkedlifedata.com/resource/pubmed/chemical/Multienzyme Complexes,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B,
http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex,
http://linkedlifedata.com/resource/pubmed/chemical/Tetradecanoylphorbol Acetate,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
May
|
| pubmed:issn |
0006-2952
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
1
|
| pubmed:volume |
55
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1391-7
|
| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:10076530-Adenosine Triphosphatases,
pubmed-meshheading:10076530-Animals,
pubmed-meshheading:10076530-Brain,
pubmed-meshheading:10076530-Calpain,
pubmed-meshheading:10076530-Cattle,
pubmed-meshheading:10076530-Cell Division,
pubmed-meshheading:10076530-Cell Line,
pubmed-meshheading:10076530-Cysteine Endopeptidases,
pubmed-meshheading:10076530-Cysteine Proteinase Inhibitors,
pubmed-meshheading:10076530-Dipeptides,
pubmed-meshheading:10076530-Female,
pubmed-meshheading:10076530-Lipopolysaccharides,
pubmed-meshheading:10076530-Macrophages,
pubmed-meshheading:10076530-Mice,
pubmed-meshheading:10076530-Multienzyme Complexes,
pubmed-meshheading:10076530-NF-kappa B,
pubmed-meshheading:10076530-Phosphorylation,
pubmed-meshheading:10076530-Proteasome Endopeptidase Complex,
pubmed-meshheading:10076530-Signal Transduction,
pubmed-meshheading:10076530-Structure-Activity Relationship,
pubmed-meshheading:10076530-Tetradecanoylphorbol Acetate,
pubmed-meshheading:10076530-Tumor Necrosis Factor-alpha
|
| pubmed:year |
1998
|
| pubmed:articleTitle |
A new structural class of proteasome inhibitors that prevent NF-kappa B activation.
|
| pubmed:affiliation |
CV Therapeutics, Inc., Palo Alto, CA 94304, USA.
|
| pubmed:publicationType |
Journal Article
|