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.
Keywords:
ASK1 inhibitors; Synthesis; biological evaluation; quinoxaline derivatives.
MeSH terms
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Cell Line
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Cell Survival / drug effects
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Dose-Response Relationship, Drug*
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Humans
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MAP Kinase Kinase Kinase 5* / antagonists & inhibitors
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MAP Kinase Kinase Kinase 5* / metabolism
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Molecular Structure
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Protein Kinase Inhibitors* / chemical synthesis
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Protein Kinase Inhibitors* / chemistry
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Protein Kinase Inhibitors* / pharmacology
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Quinoxalines* / chemical synthesis
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Quinoxalines* / chemistry
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Quinoxalines* / pharmacology
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Structure-Activity Relationship
Substances
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Quinoxalines
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MAP Kinase Kinase Kinase 5
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Protein Kinase Inhibitors
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MAP3K5 protein, human
Grants and funding
This work was supported by the National Natural Science Foundation of China (NSFC) (No. 22067010), Jiangxi Province Traditional Chinese Medicine Young and Middle-aged Backbone Talents Training Program (Fourth Batch) (Document No. 7 of Gan Traditional Chinese Medicine Science and Education [2022]), Jiangxi University of Chinese Medicine School-level Science and Technology Innovation Team Development Program (No. CXTD22005), the General Program of Jiangxi Natural Science Foundation (No. 20224BAB206117), the PhD Start-Up Fund of Jiangxi University of Chinese Medicine (No. 2021BSZR024), and the Jiangxi Provincial Key Laboratory of TCM Female Reproductive Health and Related Diseases Research and transformation (No. 2024SSY06311).