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Abstract #25258 Published in IGR 12-1
Characterization of a novel non-steroidal glucocorticoid receptor antagonist
Li Q -Y; Zhang M; Hallis T M; DeRosier T A; Yue J -M; Ye Y; Mais D E; Wang M -WBiochemical and Biophysical Research Communications 2010; 391: 1531-1536
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.
M.-W. Wang. The National Center for Drug Screening, Shanghai, China. wangmw@mail.shcnc.ac.cn
Classification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
9.4.1 Steroid-induced glaucoma (Part of: 9 Clinical forms of glaucomas > 9.4 Glaucomas associated with other ocular and systemic disorders)
