SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase

TLDR

Jun N-terminal kinase (JNK) is a stress‑activated protein kinase induced by inflammatory cytokines, bacterial endotoxin, osmotic shock, UV radiation, and hypoxia. The anthrapyrazolone SP600125 potently and selectively inhibits JNK1–3 (Ki = 0.19 µM), reversibly blocks ATP binding, suppresses c‑Jun phosphorylation and inflammatory gene expression in cells, reduces LPS‑induced TNF‑α in animals, and protects thymocytes from anti‑CD3‑induced apoptosis, underscoring JNK inhibition as a therapeutic strategy for inflammation, apoptosis, and cancer.

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.