Endocrine Abstracts

Glucocorticoid receptor (GR) agonists are amongst the most effective anti-inflammatory drugs available. These drugs are used in the treatment of a wide range of inflammatory and autoimmune diseases, and for the clinical management of cancer and organ/tissue transplantation. Unfortunately, the full clinical potential of these drugs has not been achieved, especially upon chronic use, due to the occurrence of side effects and/or resistance. The past years, most attention has focused on the development of novel compounds favoring the protein-protein interaction dependent, so-called transrepressing, actions of the glucocorticoid receptor, explaining its anti-inflammatory profile. This strategy was adopted since the DNA-dependent transactivating actions were assumed to predominantly underpin undesirable actions. Compounds with this specific profile are classified as SEGRAMs, including selective glucocorticoid receptor agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). The latter class rather modulates the activity of a GR agonist and/or may not classically bind the glucocorticoid receptor ligand-binding pocket. Although nowadays it is realized the transrepression vs transactivation concept is a too simplistic and far from watertight approach, currently developed SEGRAMs have nevertheless been helpful in elucidating various molecular actions of the glucocorticoid receptor. As could be expected, their preclinical use also provoked many novel questions.Corticosteroids currently in the clinic are used with a “one-fits-all” rationale for the treatment/management of inflammatory diseases and cancer. Glucocorticoid receptor (GR) regulation and responses are far more complex than previously recognized. GR is not a “one-fits-all” type of target, but requires a tailored approach when it comes to drug discovery to meet the new insight that GR is a receptor demonstrating a high degree of plasticity. Multiple GR conformations must exist, likely resulting in different anti-inflammatory (AI) profiles. Trying to achieve a selective GR-mediated activation of particular AI profiles may offer the potential for the development of safer and disease-tailored GR-targeting medicines.