title: SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase.
abstract: 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 (K(i) = 0.19 microM). 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-gamma, TNF-alpha, 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-alpha 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.
authors.affiliation: Signal Research Division, Celgene Corporation, 5555 Oberlin Drive, San Diego, CA 92121 USA. bbennett@signalpharm.com
authors.forename: B L
authors.initials: BL
authors.lastname: Bennett
authors.forename: D T
authors.initials: DT
authors.lastname: Sasaki
authors.forename: B W
authors.initials: BW
authors.lastname: Murray
authors.forename: E C
authors.initials: EC
authors.lastname: O'Leary
authors.forename: S T
authors.initials: ST
authors.lastname: Sakata
authors.forename: W
authors.initials: W
authors.lastname: Xu
authors.forename: J C
authors.initials: JC
authors.lastname: Leisten
authors.forename: A
authors.initials: A
authors.lastname: Motiwala
authors.forename: S
authors.initials: S
authors.lastname: Pierce
authors.forename: Y
authors.initials: Y
authors.lastname: Satoh
authors.forename: S S
authors.initials: SS
authors.lastname: Bhagwat
authors.forename: A M
authors.initials: AM
authors.lastname: Manning
authors.forename: D W
authors.initials: DW
authors.lastname: Anderson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000873:Anthracenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000880:Anthraquinones; D001667:Binding, Competitive; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D047069:Pyrazolones; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000873:Anthracenes; D000880:Anthraquinones; D016207:Cytokines; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D047069:Pyrazolones; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; C050637:losoxantrone; D000255:Adenosine Triphosphate; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases