An irreversible inhibitor of 17β-hydroxysteroid dehydrogenase type 1 inhibits estradiol synthesis in human endometriosis lesions and induces regression of the non-human primate endometriosis

Poirier, Donald; Nyachieo, Atunga; Romano, Andrea; Roy, Jenny; Maltais, René; Chai, Daniel; Delvoux, Bert; Tomassetti, Carla; Vanhie, Arne

doi:10.1016/j.jsbmb.2022.106136

Cited by 12 publications

(11 citation statements)

References 28 publications

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“…The addition of the m -carbamoylphenyl group at C3 of E1 with the formation of an ether bond (compound 5 ) slightly reduced the inhibitory activity (IC 50 = 0.21 and 0.31 μM for E1 and 5 , respectively). The inhibitory activity of compound 5 (IC 50 = 0.31 μM) is, however, close to that of the PBRM inhibitor (IC 50 = 0.15 μM), a targeted-covalent inhibitor which has demonstrated its potential during proof of concept for the treatment of breast cancer [ 37 ] and endometriosis [ 38 ]. The inhibitory capacity of E1-derivative 5, however, decreased when the ketone at C17 was reduced into 17β-alcohol (E2-derivative 6 ) (IC 50 = 0.31 and 1.2 μM, respectively).…”

Section: Resultsmentioning

confidence: 99%

“…T-47D cells were immortalized from pleural effusion of ductal carcinoma found in the mammary gland of a human patient with breast cancer. They express the estrogen receptor (ER) and 17β-HSD1, the latter enzyme being responsible for the majority of the E2 produced from E1 in this cell line [ 38 ]. Z-12 epithelial cells were immortalized from the endometrium of a human patient with endometriosis, and they express ER as well as 17β-HSD1 [ 40 , 41 ].…”

Section: Resultsmentioning

confidence: 99%

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Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone

et al. 2023

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Estradiol (E2) plays an important role in the progression of diseases such as breast cancer and endometriosis. Inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme that catalyzes the last step in the biosynthesis of the estrogenic hormone E2, therefore constitutes an interesting approach for the treatment of these two estrogen-dependent diseases. In order to obtain new inhibitors of 17β-HSD1, the impact of a m-carbamoylphenyloxy group at position three of an estrane nucleus was evaluated by preparing three derivatives of estrone (E1) and E2 using a microwave-assisted synthesis of diaryl ethers. Their inhibitory activity was addressed on two cell lines (T-47D and Z-12) representative of breast cancer and endometriosis, respectively, but unlike T-47D cells, Z-12 cells were not found suitable for testing potential 17β-HSD1 inhibitors. Thus, the addition of the m-carbamoylphenyl group at C3 of E1 (compound 5) did not increase the inhibition of E1 to E2 transformation by 17β-HSD1 present in T-47D cells (IC50 = 0.31 and 0.21 μM for 5 and E1, respectively), and this negative effect was more obvious for E2 derivatives 6 and 10 (IC50 = 1.2 and 1.3 μM, respectively). Molecular docking allowed us to identify key interactions with 17β-HSD1 and to highlight these new inhibitors’ actions through an opposite orientation than natural enzyme substrate E1′s classical one. Furthermore, molecular modeling experiments explain the better inhibitory activity of E1-ether derivative 5, as opposed to the E2-ether derivatives 6 and 10. Finally, when tested on T-47D and Z-12 cells, compounds 5, 6 and 10 did not stimulate the proliferation of these two estrogen-dependent cell lines. In fact, they reduced it.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone

et al. 2023

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“…Inhibitor 3 is less potent than inhibitor 2 in T47D cells (IC50 = 68 and 27 nM, respectively), but unlike its reversible analog 2, it did not show estrogenic activity in mice [58]. Thanks to these characteristics, inhibitor 3 was able to effectively block the growth of tumors (xenografts of T47D human cancer cells in nude mice) induced by two precursors of E2, namely E1 and DHEA [62], and has also shown its efficacy in a monkey model of endometriosis [63]. Inhibitor 4: 17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) is a membranar enzyme involved in the oxidation of key hydroxysteroids, such as E2, 5-diol, T, DHT, and 20α-DHP, to less active corresponding ketosteroids [64].…”

Section: Biological Activity Of Inhibitors 1-7 and Activatormentioning

confidence: 99%

Section: Biological Activity Of Inhibitors 1-7 and Activatormentioning

confidence: 99%

Description of Chemical Synthesis, Nuclear Magnetic Resonance Characterization and Biological Activity of Estrane-Based Inhibitors/Activators of Steroidogenesis

Poirier

2023

Molecules

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Steroid hormones play a crucial role in several aspects of human life, and steroidogenesis is the process by which hormones are produced from cholesterol using several enzymes that work in concert to obtain the appropriate levels of each hormone at the right time. Unfortunately, many diseases, such as cancer, endometriosis, and osteoporosis as examples, are caused by an increase in the production of certain hormones. For these diseases, the use of an inhibitor to block the activity of an enzyme and, in doing so, the production of a key hormone is a proven therapeutic strategy whose development continues. This account-type article focuses on seven inhibitors (compounds 1–7) and an activator (compound 8) of six enzymes involved in steroidogenesis, namely steroid sulfatase, aldo-keto reductase 1C3, types 1, 2, 3, and 12 of the 17β-hydroxysteroid dehydrogenases. For these steroid derivatives, three topics will be addressed: (1) Their chemical synthesis from the same starting material, estrone, (2) their structural characterization using nuclear magnetic resonance, and (3) their in vitro or in vivo biological activities. These bioactive molecules constitute potential therapeutic or mechanistic tools that could be used to better understand the role of certain hormones in steroidogenesis.

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“…The compound is now entering phase II of clinical development with endometriosis patients in the US to assess its efficacy as a long-term treatment option for endometriosis. A second 17β-HSD1 inhibitor that has reached the stage of in vivo testing (in murine and monkey models) is a covalent inhibitor of 17β-HSD1 (called PBRM), whose biopharmaceutical attributes and pharmacodynamics are conducive to further development. ,− …”

Section: Introductionmentioning

confidence: 99%

Dual Targeting of Steroid Sulfatase and 17β-Hydroxysteroid Dehydrogenase Type 1 by a Novel Drug-Prodrug Approach: A Potential Therapeutic Option for the Treatment of Endometriosis

et al. 2022

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A novel approach for the dual inhibition of steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1(17β HSD1) by a single drug was explored, starting from in-house 17β HSD1 inhibitors via masking their phenolic OH group with a sulfamate ester. The sulfamates were intentionally designed as drugs for the inhibition of STS and, at the same time, prodrugs for 17β-HSD1 inhibition (“drug-prodrug approach”). The most promising sulfamates 13, 16, 18–20, 22–24, 36, and 37 showed nanomolar IC50 values for STS inhibition in a cellular assay and their corresponding phenols displayed potent 17β-HSD1 inhibition in cell-free and cellular assays, high selectivity over 17β-HSD2, reasonable metabolic stability, and low estrogen receptor α affinity. A close relationship was found between the liberation of the phenolic compound by sulfamate hydrolysis and 17β-HSD1 inactivation. These results showed that the envisaged drug-prodrug concept was successfully implemented. The novel compounds constitute a promising class of therapeutics for the treatment of endometriosis and other estrogen-dependent diseases.

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An irreversible inhibitor of 17β-hydroxysteroid dehydrogenase type 1 inhibits estradiol synthesis in human endometriosis lesions and induces regression of the non-human primate endometriosis

Cited by 12 publications

References 28 publications

Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone

Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone

Description of Chemical Synthesis, Nuclear Magnetic Resonance Characterization and Biological Activity of Estrane-Based Inhibitors/Activators of Steroidogenesis

Dual Targeting of Steroid Sulfatase and 17β-Hydroxysteroid Dehydrogenase Type 1 by a Novel Drug-Prodrug Approach: A Potential Therapeutic Option for the Treatment of Endometriosis

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