First Dual Inhibitors of Steroid Sulfatase (STS) and 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1): Designed Multiple Ligands as Novel Potential Therapeutics for Estrogen-Dependent Diseases
Abstract
STS and 17β-HSD1 are attractive targets for the treatment of estrogen-dependent diseases like endometriosis and breast cancer. The simultaneous inhibition of both enzymes appears more promising than blockage of either protein alone. We describe a designed multiple ligand approach resulting in highly potent dual inhibitors. The most interesting compound 9 showed nanomolar IC 50 values for both proteins, membrane permeability, and no interference with estrogen receptors. It efficiently reversed E1S- and E1-induced T47D cell proliferation.
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A dual STS/17βHSD1 inhibitor blocks proliferation of cancer cells treated with E1S/E1 but not those treated with E2 alone.
“A dual STS/17βHSD1 inhibitor has been shown to block the proliferation of cancer cells treated with E1S/E1 but not those treated with E2 alone [109]”
From Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders (2018) · cites this paper as [109]
Cites
Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers
Purohit, A., & Foster, P. A. (2012) · Journal of Endocrinology · doi:10.1530/joe-11-0266 · Cited by 126 · see citing works
Estrogen biosynthesis and signaling in endometriosis
Huhtinen, K., Ståhle, M., Perheentupa, A., & Poutanen, M. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.08.022 · Cited by 107 · see citing works
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Current and emerging treatment options for endometriosis
Ferrero, S., Evangelisti, G., & Barra, F. (2018) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2018.1494154 · Cited by 152 · see citing works
A comprehensive review of hormonal and biological therapies for endometriosis: latest developments
Barra, F., Grandi, G., Tantari, M., Scala, C., Facchinetti, F., & Ferrero, S. (2019) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2019.1581761 · Cited by 69 · see citing works
Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders
Gibson, D. A., Simitsidellis, I., Collins, F., & Saunders, P. T. K. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103276 · Cited by 70 · see citing works
“A dual STS/17βHSD1 inhibitor has been shown to block the proliferation of cancer cells treated with E1S/E1 but not those treated with E2 alone [109], but this awaits further testing in vivo.”
BackgroundSteroid sulphatase and its inhibitors: past, present, and future
Foster, P. A. (2021) · Molecules · doi:10.3390/molecules26102852 · Cited by 49 · see citing works
Konings, G. F., Cornel, K. M., Xanthoulea, S., Delvoux, B., Skowron, M. A., Kooreman, L., Koskimies, P., Krakstad, C., Salvesen, H. B., van Kuijk, K., et al. (2018) · The Journal of Pathology · doi:10.1002/path.5004 · Cited by 26 · see citing works
Mercorio, A., Giampaolino, P., Romano, A., Dällenbach, P., & Pluchino, N. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.950866 · Cited by 16 · see citing works
- Authors
- Salah, M., Abdelsamie, A. S., & Frotscher, M.
- Affiliations
- Saarland University (DE)
- National Research Centre (EG)
- Corresponding author
- Frotscher, Martin
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-04-27
- Volume
- 60
- Issue
- 9
- Pages
- 4086-4092
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2607381088
- Cited by
- 28
- References
- 2
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 1 · 2022: 5 · 2021: 3 · 2020: 2 · 2019: 6 · 2018: 4 · 2017: 1
- FWCI
- 2.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (FR 3002/1-1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- steroid sulfatase, 17β-hydroxysteroid dehydrogenase type 1, dual enzyme inhibitors, estrogen-dependent disease, endometriosis, breast cancer, membrane permeability
- MeSH terms
- Breast Neoplasms, Endometriosis, Enzyme Inhibitors, Female, Humans, Ligands, 17-Hydroxysteroid Dehydrogenases, Steryl-Sulfatase, Cell Proliferation
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