A High‐Quality Photoswitchable Probe that Selectively and Potently Regulates the Transcription Factor RORγ

Retinoic acid receptor‐related orphan receptor γ (RORγ) is a nuclear hormone receptor with multiple biological functions. As an experimental therapeutic target in inflammation and immunity, there is great interest in spatially‐localised RORγ inhibition; and its cyclic temporal role in circadian rhythms also makes it an intriguing target for time‐resolved pharmacology. To create tools that can study RORγ biology with appropriate spatial and temporal resolution, we designed light‐dependent inverse RORγ agonists by building azobenzene photoswitches into ligand consensus structures. Optimizations gave photoswitchable RORγ inhibitors with a large degree of potency photocontrol, plus remarkable on‐target potency, plus excellent selectivity over related off‐target receptors. This still‐rare, but urgently‐needed combination of performance features, distinguishes them as high quality photopharmaceutical probes; and they can now serve as high precision tools to study the spatial and dynamic intricacies of RORγ action in signaling and in inflammatory disorders.