Optical Control of the Glucocorticoid Receptor Activity With a Photoswitchable Agonist

ABSTRACT Glucocorticoids (GCs) are widely prescribed anti‐inflammatory agents whose clinical utility is limited by systemic side effects arising from broad glucocorticoid receptor (GR) activation. Optical control of GR pharmacology offers a strategy to modulate receptor signaling with spatial and temporal resolution. Here, we report AzoCort1 , a prednisolone‐derived photopharmaceutical that enables light‐dependent tuning of GR activity in cell culture. Upon irradiation, AzoCort1 exhibits low picomolar activity (EC 50 = 11 pM) in a gene expression assay, representing a 36‐fold enhancement relative to its dark state (EC 50 = 400 pM). Despite its high potency, AzoCort1 is less efficacious in triggering glucocorticoid response element (GRE)‐driven activation compared to dexamethasone, while preserving maximal GR‐dependent repression of NF‐κB and AP‐1 signaling. These findings demonstrate light‐driven control of GR activity and separation of maximal GR‐mediated gene activation from gene repression.