SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase
SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase
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DOI：
10.1073/pnas.251194298
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发表时间：
2001-11-20
影响因子：
11.1
通讯作者：
Anderson, DW
中科院分区：
文献类型：
--
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
Jun N-末端激酶（JNK）是一种应激活化的蛋白激酶，可由炎性细胞因子、细菌内毒素、渗透压休克、紫外线辐射和缺氧诱导。我们报告了一个anthrapyrazolone系列的鉴定，具有显著的抑制JNK 1，-2，和-3（Ki = 0.19 μ M）。SP 600125是一种可逆的ATP竞争性抑制剂，对一系列激酶和酶的选择性> 20倍。在细胞中，SP 600125剂量依赖性地抑制c-Jun的磷酸化、炎性基因考克斯-2、IL-2、IFN-γ、TNF-α的表达，并阻止原代人CD 4细胞培养物的活化和分化。在动物研究中，SP 600125阻断（细菌）脂多糖诱导的肿瘤坏死因子-α表达，并抑制抗CD 3诱导的CD 4（+）CD 8（+）胸腺细胞凋亡。我们的研究支持靶向JNK作为炎症性疾病、凋亡性细胞死亡和癌症的重要策略。
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 muM). 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) lipolysaccharide-induced expression of tumor necrosis factor-alpha and inhibited antiCD3-induced apoptosis of CD4(+) CD8(+) thymocytes. Our study supports targeting JNK as an important strategy in inflammatory disease, apoptotic cell death, and cancer.