Structure-Guided Design of Nurr1 Agonists Derived from the Natural Ligand Dihydroxyindole

The neuroprotective transcription factor Nurr1 was recently
found
to bind the dopamine metabolite 5,6-dihydroxyindole (DHI) providing
access to Nurr1 ligand design from a natural template. We screened
a custom set of 14 k extended DHI analogues in silico for optimized
descendants to select 24 candidates for microscale synthesis and in
vitro testing. Three out of six primary hits were validated as novel
Nurr1 agonists with up to sub-micromolar binding affinity, highlighting
the druggability of the Nurr1 surface region lining helix 12. In vitro
profiling confirmed cellular target engagement of DHI descendants
and demonstrated remarkable additive effects of combined Nurr1 agonist
treatment, indicating diverse binding sites mediating Nurr1 activation,
which may open new avenues in Nurr1 modulation.