SP600125 是一种选择性 JNK 抑制剂,也是 NAD(P)H:醌氧化还原酶 1 (NQO1) 的强效抑制剂。

IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2024-11-25 DOI:10.1038/s41401-024-01418-1
Bing-Ling Zhong, Yi-Fei Zhang, Hao-Yi Zheng, Qiang Chen, Hua-Dong Lu, Xiu-Ping Chen
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引用次数: 0

摘要

c-Jun N 端激酶(JNKs)已被确定为多种细胞过程(包括应激刺激、炎症、细胞增殖和凋亡等)的关键调节因子。SP600125 是一种广泛使用的 ATP 竞争性可逆 JNKs 抑制剂。NAD(P)H:醌氧化还原酶1(NQO1)是一种由黄蛋白介导的醌类化合物的二电子或四电子还原酶。在这里,我们发现 SP600125 能与 NQO1 的活性口袋结合并抑制 NQO1 的活性。SP600125 对 NQO1 介导的醌类生物活化、H2O2 生成和细胞死亡的抑制作用与特异性 NQO1 抑制剂双香豆素(DIC)相当。重要的是,SP600125 对 NQO1 的抑制作用与 JNKs 抑制作用无关。这些结果表明,SP600125是一种新型的NQO1抑制剂,这为研究SP600125的作用机制提供了新的视角。此外,SP600125作为一种JNKs抑制剂应更加谨慎,尤其是在NQO1高表达的情况下。SP600125能与β-Lap(NQO1生物激活药物)竞争结合到NQO1上,并抑制NQO1依赖性细胞死亡。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
SP600125, a selective JNK inhibitor, is a potent inhibitor of NAD(P)H: quinone oxidoreductase 1 (NQO1).

The c-Jun N-terminal kinases (JNKs) has been identified as a critical modulator in multiple cellular processes, including stress stimulus, inflammation, cell proliferation, apoptosis, etc. SP600125 is a widely used ATP-competitive reversible JNKs inhibitor. NAD(P)H: quinone oxidoreductase 1 (NQO1) is a flavoprotein mediated two or four electron-reduction of quinones. Here, we showed that SP600125 bind to the active pocket of NQO1 and inhibit NQO1 activity. SP600125 exhibits comparable inhibitory effects on NQO1-mediated quinone bioactivation, H2O2 generation, and cell death, as the specific NQO1 inhibitor dicoumarol (DIC). Importantly, the inhibitory effects of SP600125 on NQO1 are independent of JNKs inhibition. These results suggested that SP600125 is a novel NQO1 inhibitor, which provides new insights into the mechanism of action of SP600125. Furthermore, SP600125 should be used more cautiously as a JNKs inhibitor, especially when NQO1 is highly expressed. SP600125 competed with β-Lap (NQO1-bioactivated drugs) for binding to NQO1, and inhibited NQO1-dependent cell death.

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来源期刊
Acta Pharmacologica Sinica
Acta Pharmacologica Sinica 医学-化学综合
CiteScore
15.10
自引率
2.40%
发文量
4365
审稿时长
2 months
期刊介绍: APS (Acta Pharmacologica Sinica) welcomes submissions from diverse areas of pharmacology and the life sciences. While we encourage contributions across a broad spectrum, topics of particular interest include, but are not limited to: anticancer pharmacology, cardiovascular and pulmonary pharmacology, clinical pharmacology, drug discovery, gastrointestinal and hepatic pharmacology, genitourinary, renal, and endocrine pharmacology, immunopharmacology and inflammation, molecular and cellular pharmacology, neuropharmacology, pharmaceutics, and pharmacokinetics. Join us in sharing your research and insights in pharmacology and the life sciences.
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