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

Abdelrahman Mohamed, Mohamed Salah, Mariam Tahoun, Manuel Hawner, Ahmed S. Abdelsamie, Martin Frotscher
Journal of medicinal chemistry · 2022 · vol. 65(17) , pp. 11726–11744 · doi:10.1021/acs.jmedchem.2c00589 · PMID:35993890 · W4292608044
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

This study developed a novel drug-prodrug strategy to simultaneously inhibit steroid sulfatase and 17β-hydroxysteroid dehydrogenase type 1, showing promise for endometriosis treatment.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-07 · read from full text ⓘ

The paper describes a novel drug–prodrug strategy intended to dual-target steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), based on enzyme inhibition assays using radiolabeled substrates. In human T47D breast cancer cells, the compounds produced low-nanomolar to sub–100 nM IC50 values for STS inhibition measured after 24 hours, including conditions described as irreversible inhibition, and they also inhibited 17β-HSD1 with IC50 values spanning from low nanomolar to well above 100 nM depending on the assay system and format; 17β-HSD1 activity was measured both in T47D cells after 24 hours and in human placental cytosol fractions after 10 minutes. A major limitation explicitly evident from the provided text is that it reports only in vitro affinity/enzyme inhibition data without any in vivo efficacy, pharmacokinetics, safety, or mechanistic confirmation of prodrug activation. Relevance to endometriosis: the title and stated therapeutic intent explicitly frame the approach as a potential therapeutic option for endometriosis through dual inhibition of estrogen-regulating enzymes.

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Abstract

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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Report error Found 86 Enz. Inhib. hit(s) with all data for entry = 50016537 Affinity DataIC50: 2.60nMAssay Description:Irreversible inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 2.70nMAssay Description:Inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 2.70nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NADH measured after 10 mins by HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 7.60nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 8.10nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NADH measured after 10 mins by HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 8.60nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 10nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 10nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 11nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NADH measured after 10 mins by HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 12nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 12nMAssay Description:Inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 12nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 14nMAssay Description:Inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 14nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 15nMAssay Description:Irreversible inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 16nMAssay Description:Irreversible inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 17nMAssay Description:Inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 17nMAssay Description:Irreversible inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 21nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 22nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NADH measured after 10 mins by HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 23nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NADH measured after 10 mins by HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 25nMAssay Description:Irreversible inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 25nMAssay Description:Inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 27nMAssay Description:Inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 27nMAssay Description:Irreversible inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 27nMAssay Description:Inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 28nMAssay Description:Inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 29nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 29nMAssay Description:Irreversible inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 31nMAssay Description:Irreversible inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 32nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NADH measured after 10 mins by HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 34nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NADH measured after 10 mins by HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 40nMAssay Description:Inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 41nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NADH measured after 10 mins by HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 43nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 50nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 52nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 55nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NADH measured after 10 mins by HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 60nMAssay Description:Irreversible inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 60nMAssay Description:Inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 63nMAssay Description:Inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 64nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 68nMAssay Description:Irreversible inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 110nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 120nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 130nMAssay Description:Inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 150nMAssay Description:Inhibition of STS in human T47D cells using [3H]E1S as substrate measured after 24 hrs by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 150nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NADH measured after 10 mins by HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 160nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NADH measured after 10 mins by HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 170nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NADH measured after 10 mins by HPLC methodMore data for this Ligand-Target Pair

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mesh:D004715endometriosis

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Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Prodrugs Prodrugs Prodrugs Prodrugs Prodrugs Prodrugs Prodrugs Prodrugs

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