Cushing’s Syndrome (CS) is caused by the pathological dysregulation of glucocorticoid (GC) hormone secretion. Although surgery remains the first-line treatment for CS, it is not always feasible and often unsuccessful. The glucocorticoid receptor (GR) antagonist mifepristone is used in the United States as a drug treatment for patients with CS. Unfortunately, mifepristone disinhibits the HPA axis, resulting in increased ACTH and cortisol secretion. Furthermore, it exhibits cross-reactivity with the progesterone receptor (PR), generally increasing the risk of adverse side effects due to the lack of GR selectivity. Relacorilant is a highly selective GR antagonist that is currently undergoing phase 3 clinical evaluation for the treatment of CS. In this study, we set out to further characterize relacorilant in comparison to mifepristone in a series of preclinical studies.

Relacorilant potently antagonized dexamethasone- and cortisol-induced GR signaling in human HEK-293 cells and largely prevented the anti-inflammatory effects of dexamethasone in human peripheral blood mononuclear cells. In mice, relacorilant treatment prevented hyperinsulinemia and immunosuppression caused by excessive GC exposure. After novelty stress exposure, relacorilant only induced a modest disinhibition of the HPA axis, in contrast with mifepristone which strongly disinhibited the HPA axis. In line with this, relacorilant was generally less potent than mifepristone in regulating Pomc mRNA and ACTH release in mouse pituitary cells. Relacorilant treatment reduced the expression of classical GR target genes in peripheral tissues but not in the brain, which may also contribute to less disinhibition of the HPA axis. These differences between relacorilant and mifepristone are possibly due to distinct transcriptional coregulator recruitment, which we observed in our high-throughput GR interaction profiling. Altogether, the distinct properties of relacorilant support its potential use as a selective GR antagonist treatment for CS.