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

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.