First irreversible and selective inhibitor of 17β-HSD1 for treatment of breast cancer and endometriosis
Type 1 17β-hydroxystéroid dehydrogenase (17β-HSD1) is an enzyme highly expressed 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 Donald Poirier has developed the first known irreversible inhibitor of 17β-HSD1 that is orally bioavailable and displays no 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-HSDs, CYP450s, and hERG.
Poirier D, J Roy, and R Maltais (2012-2019). Inhibitors of 17ß-HSD1, 17ß-HSD3 and 17ß-HSD10. WO2012129673A1, CA2830984A1, US20140088053A1, JP2018062523A, EP2688901B1. Assignee: Université Laval.
Maltais R, A Trottier, J Roy, D Ayan, N Bertrand, and D Poirier (2018). Pharmacokinetic profile of PBRM in rodents, a first selective covalent inhibitor of 17β-HSD1 for breast cancer and endometriosis treatments. J Steroid Biochem Mol Biol 178: 167-176.
Perreault M, R Maltais, J Roy, S Picard, I Popa, N Bertrand, and D Poirier (2019). Induction of endoplasmic reticulum stress by aminosteroid derivative RM-581 leads to tumor regression in PANC-1 xenograft model. Invest New Drugs 37: 431-440.
Trottier A, R Maltais, D Ayan, X Barbeau, J Roy, M Perreault, R Poulin, P Lagüe, and D Poirier (2017). Insight into the mode of action and selectivity of PBRM, a covalent steroidal inhibitor of 17β-hydroxysteroid dehydrogenase type 1. Biochem Pharmacol 144: 149-161.
SOVAR and Université Laval seek a partner for co-development, licensing, or commercialization of this technology.