Synthesis and biological evaluation of quinoxaline derivatives as ASK1 inhibitors.

IF 5.6 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-21 DOI:10.1080/14756366.2024.2414382

Xiaorui Han, Pingping Lan, Qianfeng Chen, Hua Liu, Zhongwen Chen, Tiantian Wang, Zengtao Wang

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Abstract

Inhibiting apoptosis signal regulated kinase 1 (ASK1) is an attractive strategy for treating diseases such as non-alcoholic steatohepatitis and multiple sclerosis. Here, we report the discovery of a dibromo substituted quinoxaline fragment containing 26e as an effective small-molecule inhibitor of ASK1, with an IC₅₀ value of 30.17 nM. In addition, the cell survival rate of 26e at different concentrations was greater than 80%, especially at 0.4 μM. Its cell survival rate was significantly higher than GS-4997, indicating its good safety in normal human liver LO2 cells. The Oil Red O staining experiment showed that 26e decreased the lipid droplets in a dose-dependent manner. Further biochemical analyses revealed that 26e could reduce the content of T-CHO, LDL, and TG in FFA-induced LO2 cells, and had the potential to treat non-alcoholic fatty disease. These findings provide a good choice for the future development of ASK1 inhibitors.

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作为 ASK1 抑制剂的喹喔啉衍生物的合成和生物学评价。

抑制凋亡信号调控激酶 1（ASK1）是治疗非酒精性脂肪性肝炎和多发性硬化症等疾病的一种有吸引力的策略。在此，我们报告发现了一种含有 26e 的二溴取代喹喔啉片段，它是一种有效的 ASK1 小分子抑制剂，IC50 值为 30.17 nM。此外，26e 在不同浓度下的细胞存活率均大于 80%，尤其是在 0.4 μM 时。其细胞存活率明显高于 GS-4997，表明其在正常人肝脏 LO2 细胞中具有良好的安全性。油红 O 染色实验表明，26e 能以剂量依赖的方式减少脂滴。进一步的生化分析表明，26e 能降低 FFA 诱导的 LO2 细胞中 T-CHO、LDL 和 TG 的含量，具有治疗非酒精性脂肪病的潜力。这些发现为今后开发 ASK1 抑制剂提供了一个很好的选择。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Enzyme Inhibition and Medicinal Chemistry 医学-生化与分子生物学

CiteScore

10.30

自引率

10.70%

发文量

195

审稿时长

4-8 weeks

期刊介绍： Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.