{"title":"作为 ASK1 抑制剂的喹喔啉衍生物的合成和生物学评价。","authors":"Xiaorui Han, Pingping Lan, Qianfeng Chen, Hua Liu, Zhongwen Chen, Tiantian Wang, Zengtao Wang","doi":"10.1080/14756366.2024.2414382","DOIUrl":null,"url":null,"abstract":"<p><p>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 <b>26e</b> as an effective small-molecule inhibitor of ASK1, with an IC<sub>50</sub> value of 30.17 nM. In addition, the cell survival rate of <b>26e</b> at different concentrations was greater than 80%, especially at 0.4 μM. Its cell survival rate was significantly higher than <b>GS-4997</b>, indicating its good safety in normal human liver LO2 cells. The Oil Red O staining experiment showed that <b>26e</b> decreased the lipid droplets in a dose-dependent manner. Further biochemical analyses revealed that <b>26e</b> 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.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2414382"},"PeriodicalIF":5.6000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494716/pdf/","citationCount":"0","resultStr":"{\"title\":\"Synthesis and biological evaluation of quinoxaline derivatives as ASK1 inhibitors.\",\"authors\":\"Xiaorui Han, Pingping Lan, Qianfeng Chen, Hua Liu, Zhongwen Chen, Tiantian Wang, Zengtao Wang\",\"doi\":\"10.1080/14756366.2024.2414382\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 <b>26e</b> as an effective small-molecule inhibitor of ASK1, with an IC<sub>50</sub> value of 30.17 nM. In addition, the cell survival rate of <b>26e</b> at different concentrations was greater than 80%, especially at 0.4 μM. Its cell survival rate was significantly higher than <b>GS-4997</b>, indicating its good safety in normal human liver LO2 cells. The Oil Red O staining experiment showed that <b>26e</b> decreased the lipid droplets in a dose-dependent manner. Further biochemical analyses revealed that <b>26e</b> 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.</p>\",\"PeriodicalId\":15769,\"journal\":{\"name\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"volume\":\"39 1\",\"pages\":\"2414382\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2024-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494716/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/14756366.2024.2414382\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/10/21 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Enzyme Inhibition and Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/14756366.2024.2414382","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/21 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Synthesis and biological evaluation of quinoxaline derivatives as ASK1 inhibitors.
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.
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.
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