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.