Development and Profiling of Inverse Agonist Tools for the Neuroprotective Transcription Factor Nurr1

The ligand-sensing
transcription factor nuclear receptor related
1 (Nurr1) evolves as an appealing target to treat neurodegenerative
diseases. Despite its therapeutic potential observed in various rodent
models, potent modulators for Nurr1 are lacking as pharmacological
tools. Here, we report the structure–activity relationship
and systematic optimization of indole-based inverse Nurr1 agonists.
Optimized analogues decreased the receptor’s intrinsic transcriptional
activity by up to more than 90% and revealed preference for inhibiting
Nurr1 monomer activity. In orthogonal cell-free settings, we detected
displacement of NCoRs and disruption of the Nurr1 homodimer as molecular
modes of action. The inverse Nurr1 agonists reduced the expression
of Nurr1-regulated genes in T98G cells, and treatment with an inverse
Nurr1 agonist mimicked the effect of Nurr1 silencing on interleukin-6
release from LPS-stimulated human astrocytes. The indole-based inverse
Nurr1 agonists valuably extend the toolbox of Nurr1 modulators to
further probe the role of Nurr1 in neuroinflammation, cancer, and
beyond.