Identification of Inhibitors for MDM2 Ubiquitin Ligase Activity from Natural Product Extracts by a Novel High-Throughput Electrochemiluminescent Screen
| Autor: | Christy A. Sasiela, Yili Yang, David Stewart, Jirouta Kitagaki, Pankaj Oberoi, John A. Beutler, Yassamin J. Safiran, Ilia Davydov, Allan M. Weissman, James B. McMahon, Barry R. O'Keefe, Ekaterina I. Goncharova |
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| Rok vydání: | 2008 |
| Předmět: |
Proteasome Endopeptidase Complex
Programmed cell death High-throughput screening Drug Evaluation Preclinical Complex Mixtures Biochemistry Analytical Chemistry Mice chemistry.chemical_compound Ubiquitin Animals Bioassay Cell Line Transformed Biological Products Natural product Cell Death biology Caspase 3 Ubiquitination Proto-Oncogene Proteins c-mdm2 Antimicrobial Secologanin Tryptamine Alkaloids chemistry Cell culture Luminescent Measurements biology.protein Molecular Medicine Mdm2 Biological Assay Poly(ADP-ribose) Polymerases Tumor Suppressor Protein p53 Protein Processing Post-Translational Biotechnology |
| Zdroj: | SLAS Discovery. 13:229-237 |
| ISSN: | 2472-5552 |
| DOI: | 10.1177/1087057108315038 |
| Popis: | High-throughput screening technologies have revolutionized the manner in which potential therapeutics are identified. Although they are the source of lead compounds for ~65% of anticancer and antimicrobial drugs approved by the Food and Drug Administration between 1981 and 2002, natural products have largely been excluded from modern screening programs. This is due, at least in part, to the inherent difficulties in testing complex extract mixtures, which often contain nuisance compounds, in modern bioassay systems. In this article, the authors present a novel electrochemiluminescent assay system for inhibition of MDM2 activity that is suitable for testing natural product extracts in high-throughput screening systems. The assay was used to screen more than 144,000 natural product extracts. The authors identified 1 natural product, sempervirine, that inhibited MDM2 auto-ubiquitination, MDM2-mediated p53 degradation, and led to accumulation of p53 in cells. Sempervirine preferentially induced apoptosis in transformed cells expressing wild-type p53, suggesting that it could be a potential lead for anticancer therapeutics. |
| Databáze: | OpenAIRE |
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