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.

Rational Design of a New RXR Agonist Scaffold Enabling Single-Subtype Preference for RXRα, RXRß, and RXRγ.

The three retinoid X receptor subtypes (RXRα, RXRß, RXRγ) exhibit critical regulatory roles in cell proliferation and differentiation, metabolism, and inflammation. Due to their importance in nuclear receptor signaling, RXRs are widely distributed and pan-RXR agonists cause adverse effects, but the three highly conserved RXR ligand binding sites render the development of subtype-selective ligands a major challenge. We have fused elements of known RXR ligands to obtain a new RXR agonist chemotype on which minor structural modifications enabled the development of tools with single-subtype preference for RXRα, RXRß, and RXRγ. Molecular modeling indicated different binding conformations and interaction patterns with the RXR LBDs as factors of preferential binding. In a phenotypic adipocyte differentiation experiment, only the RXRα preferential tool enhanced the adipogenic effects of pioglitazone, suggesting this subtype as particularly relevant in adipogenesis and highlighting the set of subtype-preferential RXR agonist tools as suitable for functional cellular studies.