First selective covalent inhibitor of 17b-HSD1 for treatment and diagnosis of breast cancer and endometriosis
A novel therapeutic option to inhibit the production of estradiol
The 17β-HSD1 enzyme is expressed largely in estrogen-dependent tissues of breast cancer, endometrial cancer, and endometriosis lesions. However, no inhibitor has still reached the clinical trial stage due to a lack of orally active and non-estrogenic candidates. Such an inhibitor of 17β-HSD1 would provide the ability to locally regulate estradiol without affecting systemic estrogen production. This selective action suggests an important advantage compared to other hormone treatments currently used, which cause global and non-specific blockage of both estrogen receptor action and ovarian estrogen production.
The team of Prof Poirier has developed the first known irreversible inhibitor of 17β-HSD1 that is orally bioavailable and also without estrogenic activity. This novel class of inhibitor could have important advantages by lowering the dose and frequency of drug administration, as well as potential indication for radioimaging in a diagnostic purpose. The lead candidate, orally available in mice and rat, has a high maximum tolerable dose in mice and shows selectivity toward other 17β-HSD’s, CYPs and hERG.
Donald Poirier, Jenny Roy, and René Maltais (2012). Inhibitors of 17ß-HSD1, 17ß-HSD3 and 17ß-HSD10. WO2012129673A1. Assignee: Université Laval.