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Identification of Indoquinazoline Derivatives as Novel NR4A1 Agonists by Suppressing Adipocyte Lipogenesis for Treatment of Obesity

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Název: Identification of Indoquinazoline Derivatives as Novel NR4A1 Agonists by Suppressing Adipocyte Lipogenesis for Treatment of Obesity
Autoři: Yu-Tao Hu, Jia-Chun Luo, Shu-Min Xu, Zhi Jiang, Yu-Wei Lin, Yi-Xian Li, Jia-Heng Tan, Shuo-Bin Chen, Zhi-Shu Huang
Rok vydání: 2025
Témata: Biochemistry, Medicine, Cell Biology, Genetics, Molecular Biology, Pharmacology, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, thereby inhibiting triglyceride, targeting antiobesity agents, suppressing adipocyte lipogenesis, previous research identified, mediated transcriptional repression, mechanistic studies showed, l1 cell model, effective antiobesity therapies, direct molecular target, promising therapeutic strategy, based protein profiling, nr4a1 binding affinity, suppressed lipid anabolism, r17 , obesity developing safe, novel nr4a1 agonists, promising lead, based compound, novel class, novel agonist, nr4a1 activation, significant lipid
Popis: Developing safe and effective antiobesity therapies through lipid metabolism regulation remains challenging. Our previous research identified the indolequinazoline-based compound R17 as a promising lead with significant lipid-lowering activity in a 3T3-L1 cell model, but its direct molecular target was unknown. In this study, we demonstrate that R17 is a novel agonist of the nuclear receptor subfamily 4 group A member 1 (NR4A1) by activity-based protein profiling (ABPP) as well as the validation of targets and pharmacological effects both intracellularly and extracellularly. It has been reported the ameliorative effect of NR4A1 activation on obesity. Further mechanistic studies showed that R17 suppressed lipid anabolism-related genes through NR4A1-mediated transcriptional repression, thereby inhibiting triglyceride (TG) accumulation. Furthermore, we established a correlation between the NR4A1 binding affinity of R17 derivatives and their lipid-lowering potency. These findings highlight R17 derivatives as a novel class of NR4A1-targeting antiobesity agents and support pharmacological NR4A1 activation as a promising therapeutic strategy.
Druh dokumentu: article in journal/newspaper
Jazyk: unknown
Relation: https://figshare.com/articles/journal_contribution/Identification_of_Indoquinazoline_Derivatives_as_Novel_NR4A1_Agonists_by_Suppressing_Adipocyte_Lipogenesis_for_Treatment_of_Obesity/29920665
DOI: 10.1021/acs.jmedchem.5c00895.s003
Dostupnost: https://doi.org/10.1021/acs.jmedchem.5c00895.s003
https://figshare.com/articles/journal_contribution/Identification_of_Indoquinazoline_Derivatives_as_Novel_NR4A1_Agonists_by_Suppressing_Adipocyte_Lipogenesis_for_Treatment_of_Obesity/29920665
Rights: CC BY-NC 4.0
Přístupové číslo: edsbas.29363B8F
Databáze: BASE
Popis
Abstrakt:Developing safe and effective antiobesity therapies through lipid metabolism regulation remains challenging. Our previous research identified the indolequinazoline-based compound R17 as a promising lead with significant lipid-lowering activity in a 3T3-L1 cell model, but its direct molecular target was unknown. In this study, we demonstrate that R17 is a novel agonist of the nuclear receptor subfamily 4 group A member 1 (NR4A1) by activity-based protein profiling (ABPP) as well as the validation of targets and pharmacological effects both intracellularly and extracellularly. It has been reported the ameliorative effect of NR4A1 activation on obesity. Further mechanistic studies showed that R17 suppressed lipid anabolism-related genes through NR4A1-mediated transcriptional repression, thereby inhibiting triglyceride (TG) accumulation. Furthermore, we established a correlation between the NR4A1 binding affinity of R17 derivatives and their lipid-lowering potency. These findings highlight R17 derivatives as a novel class of NR4A1-targeting antiobesity agents and support pharmacological NR4A1 activation as a promising therapeutic strategy.
DOI:10.1021/acs.jmedchem.5c00895.s003