Nuclear receptors: Choosing the right path
A new compound modulates inflammation via oestrogen receptor pathway-selective signaling.
A compound that acts via the oestrogen receptor (ER) to selectively inhibit nuclear factor- B (NF-B) without displaying classical oestrogenic side effects could be used to treat chronic inflammatory disorders such as inflammatory bowel disease (IBD), according to a recent paper in the Proceedings of the National Academy of Sciences. Oestrogens have a wide variety of biological effects and although many of them are beneficial, oestrogen therapy has been associated with side effects such as uterine bleeding, increased risk of endometrial cancer and venous thrombosis. This has led to a search for ER ligands that retain beneficial properties but without the side effects.
 |  |
Non-selective oestrogens (those that bind both ER and ER with equal affinity) are known to have anti-inflammatory activity that is thought to result from interference with the NF-B signalling pathway. Douglas C. Harnish and colleagues therefore set out to identify ER ligands that inhibited NF-B without displaying any conventional oestrogenic functions and identified a first-in-class pathway-selective group of ER ligands.
The authors used cells transiently expressing ER or ER and an NF-B–luciferase reporter gene that was induced by interleukin-1 (IL-1) to identify compounds that inhibited NF-B activity. The first compound they discovered was WAY-169916, a non-steroidal, orally active molecule that inhibited 50% of IL-1-stimulated NF-B activity, without affecting a marker of conventional oestrogenic activity. They then studied the pathway-selectivity of this compound in vivo using a high-fat-diet mouse model in which NF-B and other inflammatory genes are upregulated in the liver. Daily treatment of ovariectomized mice with either 17-ethynyloestradiol (EE) or WAY-169916 significantly inhibited the high-fat-diet-induced expression of these genes, but, significantly, WAY-169916 did so without the accompanying oestrogenic effects observed with EE.
The potential of WAY-169916 as an anti-inflammatory therapy for IBD was then demonstrated using the HLA-B27 transgenic rat model. The transgenic rat expresses human proteins that provoke a misdirected immune response, the first stage of which is chronic intestinal inflammation. This phenotype serves as a model of IBD in which low doses of EE have been shown to be effective, and so lends itself to studies of WAY-169916.
Treatment with WAY-169916 had a positive outcome on the disease phenotype: it rapidly halted chronic diarrhoea and significantly reduced all histological parameters of intestinal inflammation to an extent comparable with EE. Co-administration of an ER antagonist showed that these effects resulted from ER activity. In addition to its potential development as an anti-inflammatory drug, WAY-169916 could provide insight into the molecular mechanism of the divergent roles of the ER.
Joanna Owens
References
- Chadwick, C. C. et al. Identification of pathway-selective estrogen receptor ligands that inhibit NF-B transcriptional activity. Proc. Natl Acad. Sci. USA 102, 2543–2548 (2005) | Article | PubMed |
- Gronemeyer, H. et al. Principles for modulation of the steroid hormone receptor superfamily. Nature Rev. Drug Discov. 3, 950–964 (2004) | Article | PubMed |
 more stories
| 
