The selective glucocorticoid receptor antagonist CORT125281 has tissue-specific activity

Abstract

Glucocorticoids mediate numerous essential processes in the human body via binding to the glucocorticoid receptor (GR). Excessive GR signaling can cause disease, and GR antagonists can be used to treat many symptoms of glucocorticoid-induced pathology. The purpose of this study was to characterize the tissue-specific properties of the selective GR antagonist CORT125281. We evaluated the antagonistic effects of CORT125281 upon acute and subchronic corticosterone exposure in mice. In the acute corticosterone setting, hypothalamus-pituitary-adrenal-axis activity was investigated by measurement of basal- and stress-induced corticosterone levels, adrenocorticotropic hormone levels and pituitary proopiomelanocortin expression. GR signaling was evaluated by RT-PCR analysis of GR-responsive transcripts in liver, muscle, brown adipose tissue (BAT), white adipose tissue (WAT) and hippocampus. Pretreatment with a high dose of CORT125281 antagonized GR activity in a tissue-dependent manner. We observed complete inhibition of GR-induced target gene expression in the liver, partial blockade in muscle and BAT and no antagonism in WAT and hippocampus. Tissue distribution only partially explained the lack of effective antagonism. CORT125281 treatment did not disinhibit the hypothalamus-pituitary-adrenal neuroendocrine axis. In the subchronic corticosterone setting, CORT125281 partially prevented corticosterone-induced hyperinsulinemia, but not hyperlipidemia and immune suppression. In conclusion, CORT125281 antagonizes GR transcriptional activity in a tissue-dependent manner and improves corticosterone-induced hyperinsulinemia. Tailored dosing of CORT125281 may allow tissue-specific inhibition of GR transcriptional activity.

Sex Differences in Brown Adipose Tissue Function: Sex Hormones, Glucocorticoids, and Their Crosstalk

“…In in vitro differentiated brown adipocytes, GCs reduced the norepinephrine-stimulated Ucp1 mRNA expression (147,149). GC inhibition of BAT activity is likely mediated through the GR since a GR-specific antagonist reversed the inhibitory effects of GC on Ucp1 mRNA expression in mice (150)(151)(152). However, it has to be kept in mind that GC can also signal through the MR, which is also expressed in BAT (130).…”

Carbonyl reductase 1 amplifies glucocorticoid action in adipose tissue and impairs glucose tolerance in lean mice

“…That 20β-DHB has divergent effects compared with other glucocorticoids and aldosterone is unsurprising given that these receptors induce ligand-specific effects [ 42 ]. The distinct nature of the transcriptional response is in part due to co-regulator recruitment [ 43 ] and although 20β-DHF on binding to MR recruited almost 93% of the co-regulators recruited by binding aldosterone or cortisol it is clear that even very small differences in co-regulator recruitment can result in a marked difference in transcriptional response [ 44 ]. Moreover, the assay that we used only probes co-regulator interactions with the receptor ligand-binding domain and not the N-terminal part of the receptor.…”

Glucocorticoid signaling delays castration-induced regression in murine models of prostate cancer

“…Castration and imaging were performed using isoflurane anesthetic, as described previously (6). In some cases, mice received 20mg/kg/day intraperitoneal injections of CORT125281 (11), which was reconstituted at 40mg/ml in DMSO and further diluted with sesame oil. All animal studies were performed in accordance with the National Institute of Health Guidelines for the Care and Use of Laboratory Animals and Use of Laboratory Animals and approved by Roswell Park Institutional Animal Care and Use Committee (1308M).…”

“…Castration and imaging were performed using isoflurane anesthetic, as described previously (Singh et al, 2015). In some cases, mice received 20mg/kg/day intraperitoneal injections of CORT125281 (Koorneef et al, 2020), which was reconstituted at 40mg/ml in DMSO and further diluted with sesame oil. At sacrifice, mouse prostate tumors were identified grossly, Supplementary Fig.…”