Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects

Abstract

Glucocorticoids (GCs) are the most commonly used antiinflammatory and immunosuppressive drugs. Their outstanding therapeutic effects, however, are often accompanied by severe and sometimes irreversible side effects. For this reason, one goal of research in the GC field is the development of new drugs, which show a reduced side-effect profile while maintaining the antiinflammatory and immunosuppressive properties of classical GCs. GCs affect gene expression by both transactivation and transrepression mechanisms. The antiinflammatory effects are mediated to a major extent via transrepression, while many side effects are due to transactivation. Our aim has been to identify ligands of the GC receptor (GR), which preferentially induce transrepression with little or no transactivating activity. Here we describe a nonsteroidal selective GR-agonist, ZK 216348, which shows a significant dissociation between transrepression and transactivation both in vitro and in vivo. In a murine model of skin inflammation, ZK 216348 showed antiinflammatory activity comparable to prednisolone for both systemic and topical application. A markedly superior sideeffect profile was found with regard to increases in blood glucose, spleen involution, and, to a lesser extent, skin atrophy; however, adrenocorticotropic hormone suppression was similar for both compounds. Based on these findings, ZK 216348 should have a lower risk, e.g., for induction of diabetes mellitus. The selective GR agonists therefore represent a promising previously undescribed class of drug candidates with an improved therapeutic index compared to classical GCs. Moreover, they are useful tool compounds for further investigating the mechanisms of GR-mediated effects.inflammation ͉ nuclear receptor ͉ dissociated glucocorticoid receptor ligand

Identification of pathway-selective estrogen receptor ligands that inhibit NF-κB transcriptional activity

“…This finding was further demonstrated by its lack of activity in a rat model of hot flush or preventing ovariectomy-induced bone loss (data not shown). This approach has also been accomplished with the glucocorticoid receptor in which two nonsteroidal ligands have been identified that are more selective for transrepression than transactivation (42,43). We believe WAY-169916 will provide a similar antiinflammatory activity without the side effects associated with either glucocorticoid or estrogen therapy.…”

A Plant-Derived Ligand Favoring Monomeric Glucocorticoid Receptor Conformation with Impaired Transactivation Potential Attenuates Collagen-Induced Arthritis

“…This insight initiated a new wave of pharmacological research directed toward the development of so-called dissociated ligands, favoring only GR-mediated transrepression of NF-B-or AP-1-driven gene expression (35)(36)(37)(38). Surprisingly, not all steroidal ligands that had dissociated properties in vitro also displayed these characteristics in vivo, especially with regard to the side-effect profile (35).…”

Corticosteroid effects on cell signalling

“…These dissociated steroids, including RU24858 and RU40066, have antiinflammatory effects in vitro [106], although there is little separation of anti-inflammatory effects and systemic sideeffects in vivo [107]. Other dissociated corticosteroids appear to show dissociation in vivo [108]. Several dissociated corticosteroids are now in clinical development and may lead to inhaled steroids with greater safety, or even to oral steroids which are less likely to produce significant adverse effects.…”