ORF39-03 - Differential Coregulator Recruitment by A Novel Glucocorticoid Receptor Modulator with Disease-Modulating Activities in Vivo

Hypercortisolism causes a wide range of symptoms including difficult to control type 2 diabetes and resistant hypertension. There is a great need for new drugs that effectively antagonize glucocorticoid receptor (GR) signaling, as the clinically approved drug mifepristone (RU-486) exhibits cross-reactivity for the progesterone receptor (PR). CORT126775 is a novel, non-steroidal and selective GR modulator. This compounds effectively antagonizes cortisol-induced GR signaling in human embryonic kidney cells with an IC50 of 9.3 nM in comparison to 3.7 nM for mifepristone, and has negligible effects on PR signaling with concentrations up to 1 µM. CORT126775 had robust disease-modulating effects in three clinically-relevant mouse models. First, at 60 and 100 mg/kg/day CORT126775 effectively prevented key metabolic symptoms associated with chronic elevated glucocorticoid (corticosterone) exposure, including elevated levels of insulin. Second, in a model of high-fat high-fructose feeding, at 60 mg/kg/day CORT126775 reversed key metabolic symptoms including elevated levels of plasma insulin, glucose and cholesterol. Third, at 60 mg/kg/day CORT126775 effectively potentiated the antitumor activity of the chemotherapeutic drug paclitaxel in MiaPaCa-xenografted mice. Mechanistically, CORT126775-bound GR showed a distinct coregulator interaction profile as compared to cortisol-GR. Despite its predominant functional GR antagonism, key agonist-like protein interactions with NCOA1/2/3 and UBE3A were preserved with CORT126775, while other known coregulator interactions including MED1, KMT2C and NROB1 were absent. Unique gain-of-function interactions for CORT126775-GR include gelsolin (GELS) and NCOA4. Proximity ligation assays confirmed the predicted ligand-specific proximity of GR for several coregulators in human A549 cells. Gelsolin knockdown did not influence GR antagonism by CORT126775 on cortisol-induced expression of canonical GR target genes, possible due to compensatory regulation by other coregulators. RNA-sequencing analysis is currently ongoing to delineate gene-specific GR antagonistic effects of CORT126775 in the absence and presence of gelsolin. In conclusion, we present a novel selective GR modulator that induces a unique GR transcription complex and that exhibits robust antagonism in vitro and in clinically-relevant disease models in vivo.