Design and development of glucocorticoid receptor modulators

Synthetic glucocorticoids (GCs) are effective anti-inflammatory drugs but cause serious adverse effects (AEs). Initially, anti-inflammatory efficacy and AEs were ascribed to GC receptor (GR)-mediated gene transrepression and transactivation, respectively. Although current evidence indicates greater mechanistic complexity of GC action, this proposed distinction in GR-mediated effects has led to the design of novel steroidal and nonsteroidal GR modulators (GRMs) using emerging technologies and new laboratory assays to reduce the AEs associated with synthetic GCs. These GRMs alter the balance between GR transrepression and transactivation. A novel GRM, the dissociated steroid vamorolone, received marketing approval in 2024, confirming that altering the transrepression-transactivation profile is a valid strategy. Here, we review GR-mediated gene regulation and the transrepression-transactivation profile of GCs in relation to their anti-inflammatory efficacy and AEs. We highlight technological advances driving the design/development of novel GRMs, such as selective GR agonists and modulators (SEGRAMs), and provide insights into their mechanism of action.