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Abstract
Retinoic acid receptor-related orphan receptor γ (RORγ) is a circadian regulator and has emerged as experimental therapeutic target in inflammation and immunity. The cyclic temporal role of RORγ in circadian rhythms makes temporally-resolved pharmacological control of this receptor particularly intriguing. To achieve next-generation tools to study RORγ biology, we designed RORγ ligands featuring a central azobenzene photoswitch, that act as light-dependent inverse agonists. Structural optimization enabled efficient photocontrol over RORγ inhibition, with remarkable potency on RORγ and excellent selectivity over related receptors. These high-specificity photopharmaceuticals can serve as high-precision tools to study the dynamic modulation of RORγ in signaling pathways and in inflammatory disorders.
