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

Salah, Mohamed; Abdelsamie, Ahmed S.; Frotscher, Martin

doi:10.1021/acs.jmedchem.7b00062

Cited by 23 publications

(32 citation statements)

References 27 publications

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“…Additionally, the development of dual/triple inhibitors, able to simultaneously target redundant intracrine pathways, is desirable. Several double STS‐aromatase inhibitors are under investigations , and very recently, the first dual 17β‐HSD‐1/STS inhibitor was developed .…”

Section: Discussionmentioning

confidence: 99%

Blocking 17β‐hydroxysteroid dehydrogenase type 1 in endometrial cancer: a potential novel endocrine therapeutic approach

Konings

Cornel

Xanthoulea

et al. 2018

The Journal of Pathology

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The enzyme type 1 17β-hydroxysteroid dehydrogenase (17β-HSD-1), responsible for generating active 17β-estradiol (E2) from low-active estrone (E1), is overexpressed in endometrial cancer (EC), thus implicating an increased intra-tissue generation of E2 in this estrogen-dependent condition. In this study, we explored the possibility of inhibiting 17β-HSD-1 and impairing the generation of E2 from E1 in EC using in vitro, in vivo, and ex vivo models. We generated EC cell lines derived from the well-differentiated endometrial adenocarcinoma Ishikawa cell line and expressing levels of 17β-HSD-1 similar to human tissues. In these cells, HPLC analysis showed that 17β-HSD-1 activity could be blocked by a specific 17β-HSD-1 inhibitor. In vitro, E1 administration elicited colony formation similar to E2, and this was impaired by 17β-HSD-1 inhibition. In vivo, tumors grafted on the chicken chorioallantoic membrane (CAM) demonstrated that E1 upregulated the expression of the estrogen responsive cyclin A similar to E2, which was impaired by 17β-HSD-1 inhibition. Neither in vitro nor in vivo effects of E1 were observed using 17β-HSD-1-negative cells (negative control). Using a patient cohort of 52 primary ECs, we demonstrated the presence of 17β-HSD-1 enzyme activity (ex vivo in tumor tissues, as measured by HPLC), which was inhibited by over 90% in more than 45% of ECs using the 17β-HSD-1 inhibitor. Since drug treatment is generally indicated for metastatic/recurrent and not primary tumor, we next demonstrated the mRNA expression of the potential drug target, 17β-HSD-1, in metastatic lesions using a second cohort of 37 EC patients. In conclusion, 17β-HSD-1 inhibition efficiently blocks the generation of E2 from E1 using various EC models. Further preclinical investigations and 17β-HSD-1 inhibitor development to make candidate compounds suitable for the first human studies are awaited. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 99%

Blocking 17β‐hydroxysteroid dehydrogenase type 1 in endometrial cancer: a potential novel endocrine therapeutic approach

Konings

Cornel

Xanthoulea

et al. 2018

The Journal of Pathology

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“…The IC50 values of the dual inhibitor 53 (figure 12) in intact T47D cells were 15 nM and 22 nM for STS and 17β-HSD1, respectively, and STS inhibition was found to be irreversible. The compound did not interfere with ERs but efficiently reversed E1S-and E1-induced T47D cell proliferation, without affecting E2-induced proliferation (Salah et al 2017).…”

Section: Dual Inhibitors Of 17β-hsd1 and Steroid Sulfatase (Sts)mentioning

confidence: 92%

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Salah

Abdelsamie²,

Frotscher

2019

Molecular and Cellular Endocrinology

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During the past 25 years, the modulation of estrogen action by inhibition of 17β-hydroxysteroid dehydrogenase types 1 and 2 (17β-HSD1 and 17β-HSD2), respectively, has been pursued intensively. In the search for novel treatment options for estrogen-dependent diseases (EDD) and in order to explore estrogenic signaling pathways, a large number of steroidal and nonsteroidal inhibitors of these enzymes has been described in the literature. The present review gives a survey on the development of inhibitor classes as well as the structural formulas and properties of their most interesting representatives. In addition, rationally designed dual inhibitors of both 17β-HSD1 and steroid sulfatase (STS) as well as the first inhibitors of 17β-HSD14 are covered.

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“…Recently, the other enzyme implicated in the hormone biosynthesis process, 17b-HSD, has reached potential therapeutic importance in the treatment of hormone-dependent diseases. Salah et al 92 reported the first dual inhibitors of STS and 17b-hydroxysteroid dehydrogenase type 1 (17b-HSD1) as promising therapeutics for oestrogen-dependent diseases. The design of dual STS/ 17b-HSD1 inhibitors was based on combining structural elements, essential for 17b-HSD1 inhibition, with the sulphamate-aryl pharmacophore (crucial in STS inactivation).…”

Section: Multitargeting Agents With Sts Inhibitory Activitiesmentioning

confidence: 99%

Recent progress in the development of steroid sulphatase inhibitors – examples of the novel and most promising compounds from the last decade

Daśko

Demkowicz

Biernacki

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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The purpose of this review article is to provide an overview of recent achievements in the synthesis of novel steroid sulphatase (STS) inhibitors. STS is a crucial enzyme in the biosynthesis of active hormones (including oestrogens and androgens) and, therefore, represents an extremely attractive molecular target for the development of hormone-dependent cancer therapies. The inhibition of STS may effectively reduce the availability of active hormones for cancer cells, causing a positive therapeutic effect. Herein, we report examples of novel STS inhibitors based on steroidal and nonsteroidal cores that contain various functional groups (e.g. sulphamate and phosphorus moieties) and halogen atoms, which may potentially be used in therapies for hormone-dependent cancers. The presented work also includes examples of multitargeting agents with STS inhibitory activities. Furthermore, the fundamental discoveries in the development of the most promising drug candidates exhibiting STS inhibitory activities are highlighted.

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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

Cited by 23 publications

References 27 publications

Blocking 17β‐hydroxysteroid dehydrogenase type 1 in endometrial cancer: a potential novel endocrine therapeutic approach

Blocking 17β‐hydroxysteroid dehydrogenase type 1 in endometrial cancer: a potential novel endocrine therapeutic approach

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Recent progress in the development of steroid sulphatase inhibitors – examples of the novel and most promising compounds from the last decade

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