Characterization of a novel non-steroidal glucocorticoid receptor antagonist

• Published in: Biochemical and biophysical research communications Vol. 391; no. 3; pp. 1531 - 1536
• Main Authors: Li, Qun-Yi, Zhang, Meng, Hallis, Tina M., DeRosier, Therese A., Yue, Jian-Min, Ye, Yang, Mais, Dale E., Wang, Ming-Wei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-01-2010
• Subjects: 60 APPLIED LIFE SCIENCES; Active Transport, Cell Nucleus - drug effects; Antagonist; APATITES; Cell Line; Cell Nucleus - metabolism; CUSHING SYNDROME; DEXAMETHASONE; Dexamethasone - antagonists & inhibitors; Dexamethasone - pharmacology; ENERGY TRANSFER; FLUORESCENCE; Gene Expression - drug effects; GENES; Glucocorticoid; Gluconeogenesis; Gluconeogenesis - drug effects; Gluconeogenesis - genetics; Humans; HYDROCORTISONE; Indoles - chemistry; Indoles - pharmacology; INFLAMMATION; LIVER; Liver - drug effects; Liver - metabolism; Matrix Metalloproteinase 9 - metabolism; METABOLIC DISEASES; MICE; NERVOUS SYSTEM DISEASES; Nuclear receptor; ONCOGENIC VIRUSES; PEPTIDES; RECEPTORS; Receptors, Glucocorticoid - antagonists & inhibitors; Receptors, Glucocorticoid - metabolism; TIME RESOLUTION; TRANSLOCATION; Xanthenes - chemistry; Xanthenes - pharmacology; Nuclear receptor; Dex; MMTV; HA; Antagonist; GR; Glucocorticoid; TR-FRET; Gluconeogenesis
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2009.12.117

Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing’s syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (
K
i
=
13.2
nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a ‘competitive’ GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.