| Novel small molecule inhibitors of caspase-3 block cellular and biochemical features of apoptosis. | |
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MedLine Citation:
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PMID: 12490620 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Caspase-3 is an intracellular cysteine protease, activated as part of the apoptotic response to cell injury. Its interest as a therapeutic target has led many to pursue the development of inhibitors. To date, only one series of nonpeptidic inhibitors have been described, and these have limited selectivity within the caspase family. Here we report the properties of a series of anilinoquinazolines (AQZs) as potent small molecule inhibitors of caspase-3. The AQZs inhibit human caspase-3 with Ki values in the 90 to 800 nM range. A subset of AQZs are equipotent against caspase-6, although most lack activity against this isoform and caspase-1, -2, -7, and -8. The AQZs inhibit endogenous caspase-3 activity toward a cell permeable, exogenously added substrate in staurosporine-treated SH-SY5Y cells. The AQZs reduce biochemical and cellular features of apoptosis that are thought to be a consequence of caspase-3 activation including DNA fragmentation, TUNEL staining, and the various morphological features that define the terminal stages of apoptotic cell death. Moreover, the AQZs also inhibit apoptosis induced by nerve growth factor withdrawal from differentiated PC12 cells. Thus, the AQZs represent a new and structurally novel class of inhibitors, some of which selectively inhibit caspase-3 and will thereby allow evaluation of the role of caspase-3 activity in various cellular models of apoptosis. |
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Authors:
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Clay W Scott; Cindy Sobotka-Briner; Deidre E Wilkins; Robert T Jacobs; James J Folmer; William J Frazee; Ratan V Bhat; Smita V Ghanekar; David Aharony |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 304 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2003 Jan |
Date Detail:
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Created Date: 2002-12-19 Completed Date: 2003-01-23 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 433-40 Citation Subset: IM |
Affiliation:
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Departments of Lead Discovery, Neuroscience, and Chemistry, AstraZeneca Pharmaceuticals, Wilmington, Delaware 19810, USA. clay.scott@astrazeneca.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Aniline Compounds
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chemical synthesis,
pharmacology* Animals Apoptosis / drug effects*, physiology Caspase 3 Caspases / antagonists & inhibitors* Cell Line Coloring Agents DNA Fragmentation / drug effects Enzyme Inhibitors / chemical synthesis, pharmacology* Fluorescent Dyes Humans In Situ Nick-End Labeling Kinetics Nerve Growth Factor / pharmacology PC12 Cells Phenotype Quinazolines / chemical synthesis, pharmacology* Rats Recombinant Proteins / metabolism Staurosporine / pharmacology Structure-Activity Relationship Swine |
| Chemical | |
Reg. No./Substance:
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0/Aniline Compounds; 0/Coloring Agents; 0/Enzyme Inhibitors; 0/Fluorescent Dyes; 0/Quinazolines; 0/Recombinant Proteins; 62996-74-1/Staurosporine; 9061-61-4/Nerve Growth Factor; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Casp3 protein, rat; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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