posted on 2021-02-25, 15:08authored bySabine Willems, Julia Ohrndorf, Whitney Kilu, Jan Heering, Daniel Merk
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.