Fragment-like Chloroquinolineamines Activate the Orphan Nuclear Receptor Nurr1 and Elucidate Activation Mechanisms

The ligand-activated transcription factor nuclear receptor related-1 (Nurr1) exhibits great potential for neurodegenerative disease treatment, but potent Nurr1 modulators to further probe and validate the nuclear receptor as a therapeutic target are lacking. We have systematically studied the structure-activity relationship of the 4-amino-7-chloroquinoline scaffold contained in Nurr1 activators amodiaquine and chloroquine and discovered fragment-like analogues that activated Nurr1 in several cellular settings. The most active descendants promoted the transcriptional activity of Nurr1 on human response elements as monomer, homodimer, and heterodimer and markedly enhanced Nurr1-dependent gene expression in human astrocytes. As a tool to elucidate mechanisms involving in Nurr1 activation, these Nurr1 agonists induced robust recruitment of NCoR1 and NCoR2 co-regulators to the Nurr1 ligand binding domain and promoted Nurr1 dimerization. These findings provide important insights in Nurr1 regulation. The fragment-sized Nurr1 agonists are appealing starting points for medicinal chemistry and valuable early Nurr1 agonist tools for pharmacology and chemical biology.