Optical Control of the Glucocorticoid Receptor Activity With a Photoswitchable Agonist.

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 (EC50 = 11 pM) in a gene expression assay, representing a 36-fold enhancement relative to its dark state (EC50 = 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.