Characterization of a novel non-steroidal glucocorticoid receptor antagonist.
Biochem Biophys Res Commun
; 391(3): 1531-6, 2010 Jan 15.
Article
in En
| MEDLINE
| ID: mdl-20035723
ABSTRACT
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)=13.2nM), 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Xanthenes
/
Receptors, Glucocorticoid
/
Gluconeogenesis
/
Indoles
/
Liver
Limits:
Humans
Language:
En
Journal:
Biochem Biophys Res Commun
Year:
2010
Document type:
Article
Affiliation country:
China