A High Throughput Screen Identifies Potent and Selective Inhibitors to Human Epithelial 15-Lipoxygenase-2
| Autor: | Auric Kantz, Matthew P. Jacobson, David J. Maloney, Chakrapani Kalyanaraman, J. Brian Jameson, Theodore R. Holman, Lena Schultz, Ajit Jadhav, Anton Simeonov |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
musculoskeletal diseases
endocrine system diseases Protein Conformation High-throughput screening Drug Evaluation Preclinical lcsh:Medicine Isozyme Biochemistry Epithelium 03 medical and health sciences Lipoxygenase chemistry.chemical_compound 0302 clinical medicine Chemical Biology Arachidonate 15-Lipoxygenase Humans Lipoxygenase Inhibitors Enzyme Inhibitors lcsh:Science 030304 developmental biology chemistry.chemical_classification Enzyme Kinetics 0303 health sciences Multidisciplinary biology integumentary system lcsh:R Hydroxyeicosatetraenoic acid food and beverages Biology and Life Sciences High-Throughput Screening Assays Molecular Docking Simulation enzymes and coenzymes (carbohydrates) Kinetics Enzyme chemistry Tumor progression 030220 oncology & carcinogenesis biology.protein Enzymology Arachidonic acid lcsh:Q Polyunsaturated fatty acid Research Article |
| Zdroj: | PLoS ONE PLoS ONE, Vol 9, Iss 8, p e104094 (2014) |
| ISSN: | 1932-6203 |
| Popis: | Lipoxygenase (LOX) enzymes catalyze the hydroperoxidation of arachidonic acid and other polyunsaturated fatty acids to hydroxyeicosatetraenoic acids with varying positional specificity to yield important biological signaling molecules. Human epithelial 15lipoxygenase2 (15-LOX-2) is a highly specific LOX isozyme that is expressed in epithelial tissue and whose activity has been correlated with suppression of tumor growth in prostate and other epithelial derived cancers. Despite the potential utility of an inhibitor to probe the specific role of 15-LOX-2 in tumor progression, no such potent/specific 15LOX2 inhibitors have been reported to date. This study employs high throughput screening to identify two novel, specific 15LOX2 inhibitors. MLS000545091 is a mixed-type inhibitor of 15-LOX-2 with a Ki of 0.9+/−0.4 µM and has a 20-fold selectivity over 5-LOX, 12-LOX, 15-LOX-1, COX-1, and COX-2. MLS000536924 is a competitive inhibitor with a Ki of 2.5+/−0.5 µM and also possesses 20-fold selectivity toward 15-LOX-2 over the other oxygenases, listed above. Finally, neither compound possesses reductive activity towards the active-site ferrous ion. |
| Databáze: | OpenAIRE |
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