SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase

doi:10.1073/pnas.251194298

SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase

Signal Research Division, Celgene Corporation, 5555 Oberlin Drive, San Diego, CA 92121

Edited by Joseph Schlessinger, Yale University School of Medicine, New Haven, CT, and approved October 1, 2001 (received for review April 19, 2001)

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 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.

Footnotes

↵ * To whom reprint requests should be addressed. E-mail: bbennett{at}signalpharm.com.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

JNK,

c-Jun N-terminal kinase;

LPS,

lipopolysaccharide;

AP-1,

activator protein-1;

ERK,

extracellular regulated kinase;

PBMC,

peripheral blood mononuclear cell;

Th0,

naïve human T cell;

TNF,

tumor necrosis factor;

ATF,

activating transcription factor