A Targeted-Covalent Inhibitor of 17β-HSD1 Blocks Two Estrogen-Biosynthesis Pathways: In Vitro (Metabolism) and In Vivo (Xenograft) Studies in T-47D Breast Cancer Models

SIMPLE SUMMARY: 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is responsible for the production of estrogens estradiol (E2) and 5-androsten-3β,17β-diol (5-diol). This enzyme is therefore a target of choice for the treatment of estrogen-dependent diseases such as breast cancer and endometriosis, by blocking estrogen biosynthesis. After we developed the first irreversible and non-estrogenic 17β-HSD1 inhibitor, a molecule named PBRM, our goal was to demonstrate its therapeutic potential. PBRM was able to block the formation of E2 and 5-diol in T-47D human breast cancer cells. When given orally to mice, PBRM was also able to block the tumor growth without any observed toxic effects. Thanks to its irreversible type of inhibition, PBRM retained its anti-tumor growth effect, even after reducing its frequency of administration to only once a week, a clear advantage over reversible inhibitors. These results strongly support the use of PBRM as a new approach in the treatment of breast cancer. ABSTRACT: 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) plays an important role in estrogen-dependent breast tumor growth. In addition to being involved in the production of estradiol (E2), the most potent estrogen in women, 17β-HSD1 is also responsible for the production of 5-androsten-3β,17β-diol (5-diol), a weaker estrogen than E2, but whose importance increases after menopause. 17β-HSD1 is therefore a target of choice for the treatment of estrogen-dependent diseases such as breast cancer and endometriosis. After we developed the first targeted-covalent (irreversible) and non-estrogenic inhibitor of 17β-HSD1, a molecule named PBRM, our goal was to demonstrate its therapeutic potential. Enzymatic assays demonstrated that estrone (E1) and dehydroepiandrosterone (DHEA) were transformed into E2 and 5-diol in T-47D human breast cancer cells, and that PBRM was able to block these transformations. Thereafter, we tested PBRM in a mouse tumor model (cell-derived T-47D xenografts). After treatment of ovariectomized (OVX) mice receiving E1 or DHEA, PBRM given orally was able to reduce the tumor growth at the control (OVX) level without any observed toxic effects. Thanks to its irreversible type of inhibition, PBRM retained its anti-tumor growth effect, even after reducing its frequency of administration to only once a week, a clear advantage over reversible inhibitors.