GR’s Role in Disease
The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily, which functions as a ligand-activated transcription factor. GR is widely expressed in various tissues and plays a vital role in regulating immune responses, stress responses, and metabolism. In its inactive state, GR resides in the cytoplasm as part of a multiprotein complex. Upon binding to glucocorticoid hormones, such as cortisol, GR undergoes a conformational change, translocates to the nucleus, and binds to specific DNA sequences known as glucocorticoid response elements (GREs). This interaction leads to the modulation of target gene transcription, influencing a wide range of physiological processes. In the absence of activated GR, other transcription factors such as NF-κB or AP-1 themselves can transactivate target genes. However activated GR can complex with these other transcription factors and prevent them from binding their target genes and hence repress the expression of genes that are normally upregulated by NF-κB or AP-1. This indirect mechanism of action is referred to as transrepression. Endogenous glucocorticoids, such as cortisol in humans and corticosterone in rodents, serve as natural ligands for GR.
GR’s Role in Drug Discovery
Interest in GR as a drug discovery target stems from its pivotal role in regulating immune responses and inflammation. Exogenous can be associated with severe side effects, including bone loss, glucocorticoids, such as prednisone and dexamethasone, are synthetic drugs used to treat various inflammatory and autoimmune conditions due to their potent anti-inflammatory and immunosuppressive properties. Synthetic glucocorticoids have been extensively used for decades in the management of inflammatory and autoimmune disorders, but their long-term use weight gain, and impaired glucose metabolism. Researchers are actively working to develop novel glucocorticoid receptor ligands that retain the beneficial anti-inflammatory effects while minimizing adverse effects. For example, CORT118335 is an investigational glucocorticoid receptor modulator being developed by Corcept Therapeutics for the treatment of Cushing's syndrome and other metabolic disorders. It has been shown to selectively modulate GR activity to reduce cortisol production while avoiding off-target effects.