SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase
| Autor: | Aparna Motiwala, Steve Pierce, Yoshitaka Satoh, Jim C. Leisten, Dennis T. Sasaki, Shripad S. Bhagwat, Eoin C. O'leary, Steve T. Sakata, Brydon L. Bennett, Brion W. Murray, David W. Anderson, Anthony M. Manning, Weiming Xu |
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| Rok vydání: | 2001 |
| Předmět: |
CD4-Positive T-Lymphocytes
Gene Expression Anthraquinones Lymphocyte Activation Binding Competitive Monocytes Proinflammatory cytokine Jurkat Cells Mice Structure-Activity Relationship Adenosine Triphosphate Animals Humans Enzyme Inhibitors Pyrazolones Protein kinase A Protein Kinase Inhibitors Cells Cultured Anthracenes Multidisciplinary biology MAP kinase kinase kinase Molecular Structure Kinase Tumor Necrosis Factor-alpha JNK Mitogen-Activated Protein Kinases Cell Differentiation Biological Sciences Molecular biology Mice Inbred C57BL c-Jun N-terminal kinases Apoptosis biology.protein Phosphorylation Cytokines Pyrazoles Tumor necrosis factor alpha Female Mitogen-Activated Protein Kinases |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 98(24) |
| ISSN: | 0027-8424 |
| Popis: | Jun N-terminal kinase (JNK) is a stress-activated protein kinase that can be induced by inflammatory cytokines, bacterial endotoxin, osmotic shock, UV radiation, and hypoxia. We report the identification of an anthrapyrazolone series with significant inhibition of JNK1, -2, and -3 (Ki= 0.19 μM). SP600125 is a reversible ATP-competitive inhibitor with >20-fold selectivity vs. a range of kinases and enzymes tested. In cells, SP600125 dose dependently inhibited the phosphorylation of c-Jun, the expression of inflammatory genesCOX-2,IL-2,IFN-γ,TNF-α, and prevented the activation and differentiation of primary human CD4 cell cultures. In animal studies, SP600125 blocked (bacterial) lipopolysaccharide-induced expression of tumor necrosis factor-α and inhibited anti-CD3-induced apoptosis of CD4+CD8+thymocytes. Our study supports targeting JNK as an important strategy in inflammatory disease, apoptotic cell death, and cancer. |
| Databáze: | OpenAIRE |
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