SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase.
Journal: 2002/January - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
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.
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Proc Natl Acad Sci U S A 98(24): 13681-13686

SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase

+4 authors
Signal Research Division, Celgene Corporation, 5555 Oberlin Drive, San Diego, CA 92121
To whom reprint requests should be addressed. E-mail: moc.mrahplangis@ttennebb.
Edited by Joseph Schlessinger, Yale University School of Medicine, New Haven, CT, and approved October 1, 2001
Edited by Joseph Schlessinger, Yale University School of Medicine, New Haven, CT, and approved October 1, 2001
Received 2001 Apr 19

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 (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.

Abstract

Inflammatory disease is characterized by greatly increased expression of multiple immune proteins that frequently result in irreparable pathology. A major focus of drug discovery efforts is the identification of small molecules that have disease-modifying activity in addition to relieving clinical symptoms. Because individual transcription factors are capable of regulating the expression of multiple genes, the signaling pathways that control the activity of these transcription factors are prime candidates for therapeutic intervention. c-Jun N-terminal kinase (JNK) is a serine threonine protein kinase that phosphorylates c-Jun (1, 2), a component of the transcription factor activator protein-1 (AP-1; refs. 3 and 4). In complex with other DNA binding proteins, AP-1 regulates the transcription of numerous genes including cytokines [e.g., IFN-γ, IL-2, and tumor necrosis factor (TNF)-α; refs. 5 and 6], growth factors [e.g., vascular endothelial growth factor (VEGF); ref. 7], immunoglobulins (e.g., κ light chain; ref. 8), inflammatory enzymes (e.g., COX-2; ref. 9), and matrix metalloproteinases (e.g., MMP-13; ref. 10). JNK is a member of the mitogen-activated protein kinase (MAPK) family that includes the extracellular regulated kinases (ERKs) and p38 kinases. Three JNK genes (JNK1, -2, and -3) have been identified in humans; however, splice variants result in a total of 10 isoforms (11). JNK1 and JNK2 have a broad tissue distribution, whereas JNK3 seems primarily localized to neuronal tissues and the cardiac myocyte (12). Mice lacking JNK1 or JNK2 exhibit deficits in T-helper (CD4) cell function (1315). Double knockout animals are embryonic lethal, although fibroblasts from these animals are viable in vitro and exhibit a remarkable resistance to radiation-induced apoptosis (16). The JNK3 knockout mouse exhibits resistance to kainic acid-induced apoptosis in the hippocampus and to subsequent seizures (17). Therefore, JNK activity seems critical for both the immune response and for programmed cell death. Therapeutic inhibition of JNK may provide clinical benefit in diseases as diverse as arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, graft vs. host disease, stroke, Parkinson's disease, ischemic injury, and myocardial infarction.

Acknowledgments

We acknowledge the enthusiasm and encouragement of Vincent Fert (SMaRT) and Bruce Seligmann (HTG). We thank Bernd Stein for critical review of this manuscript.

Acknowledgments

Abbreviations

JNKc-Jun N-terminal kinase
LPSlipopolysaccharide
AP-1activator protein-1
ERKextracellular regulated kinase
PBMCperipheral blood mononuclear cell
Th0naïve human T cell
TNFtumor necrosis factor
ATFactivating transcription factor
Abbreviations

Footnotes

This paper was submitted directly (Track II) to the PNAS office.

Footnotes

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