SP600125, An Anthrapyrazolone Inhibitor of Jun N-Terminal Kinase

• Published in: Proceedings of the National Academy of Sciences - PNAS 2001-11, Vol.98 (24), p.13681-13686
• Main Authors: Bennett, Brydon L., Sasaki, Dennis T., Murray, Brion W., O'Leary, Eoin C., Sakata, Steve T., Xu, Weiming, Leisten, Jim C., Motiwala, Aparna, Pierce, Steve, Satoh, Yoshitaka, Bhagwat, Shripad S., Manning, Anthony M., Anderson, David W.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; Anthracenes - chemistry; Anthracenes - metabolism; Anthracenes - pharmacology; Anthraquinones; Apoptosis; Binding, Competitive; Biological Sciences; Cancer; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; Cell Differentiation - drug effects; Cell growth; Cells, Cultured; Cytokines; Cytokines - metabolism; Disease; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Enzymes; Female; Gene Expression - drug effects; Humans; Inhibitory concentration 50; JNK Mitogen-Activated Protein Kinases; Jurkat Cells; Lymphocyte Activation - drug effects; Messenger RNA; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Molecular Structure; Monocytes - cytology; Monocytes - metabolism; Nervous system diseases; Phosphorylation; Protein Kinase Inhibitors; Proteins; Pyrazoles; Pyrazolones; Structure-Activity Relationship; T lymphocytes; Thymocytes; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.251194298

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 genes COX-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.