Abstract
Retinoic acid receptor-related orphan receptor γ (RORγ) is a nuclear hormone receptor with multiple biological functions in circadian clock regulation, inflammation, and immunity. Its cyclic temporal role in circadian rhythms, and cell-specific activity in the immune system, make it an intriguing target for spatially and temporally localised pharmacology. To create tools that can study RORγ biology with appropriate spatiotemporal resolution, we designed light-dependent inverse RORγ agonists by building azobenzene photoswitches into ligand consensus structures. Optimizations gave photoswitchable RORγ inhibitors combining a large degree of potency photocontrol, with remarkable on-target potency, and excellent selectivity over related off-target receptors. This still rare combination of performance features distinguishes them as high quality photopharmaceutical probes, which can now serve as high precision tools to study the spatial and dynamic intricacies of RORγ action in signaling and in inflammatory disorders.