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

Mohamed Salah, Ahmed S. Abdelsamie, Martin Frotscher
Journal of medicinal chemistry · 2017 · vol. 60(9) , pp. 4086–4092 · doi:10.1021/acs.jmedchem.7b00062 · PMID:28406629
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Researchers designed dual inhibitors of steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) that show nanomolar potency and reverse estrogen-dependent cell proliferation.

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This paper reports the identification and biochemical characterization of the first dual inhibitors targeting steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), using designed multiple-ligand approaches for estrogen-dependent diseases. In human enzyme and cell assays, compounds showed inhibitory activity against 17β-HSD1 measured with [3H]-E1/E1 substrates plus NADH via HPLC-based radio-detection, and against STS in T47D cells (and placental microsomal STS) using [3H]-E1S/E1S substrates, including time-dependent and irreversible inhibition in some STS experiments. A key limitation visible from the provided text is that it largely contains assay-readout fragments (e.g., lists of IC50 values) without full experimental design, compound structures, or in vivo/physiologic outcome context. This paper is centrally about endometriosis-adjacent estrogen-synthesis targets—specifically STS and 17β-HSD1—which are relevant to endometriosis because these enzymes modulate local estrogen availability in endometriotic tissue.

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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 IC50 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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Report error Found 51 Enz. Inhib. hit(s) with all data for entry = 50000961 Affinity DataIC50: 1.10nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 using [3H]-E1/E1 substrate and NADH after 10 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 1.40nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 using [3H]-E1/E1 substrate and NADH after 10 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 1.90nMAssay Description:Inhibition of STS in human T47D cells preincubated for 1 hr followed by addition of [3H]-E1S/E1S as substrate measured after 24 hrs by HPLC based rad...More data for this Ligand-Target Pair Affinity DataIC50: 2.10nMAssay Description:Irreversible inhibition of STS in human T47D cells preincubated for 2 hrs followed by compound washout and addition of [3H]-E1S/E1S as substrate meas...More data for this Ligand-Target Pair Affinity DataIC50: 2.10nMAssay Description:Inhibition of STS in human T47D cells preincubated for 1 hr followed by addition of [3H]-E1S/E1S as substrate measured after 24 hrs by HPLC based rad...More data for this Ligand-Target Pair Affinity DataIC50: 2.20nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 using [3H]-E1/E1 substrate and NADH after 10 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 2.5nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 using [3H]-E1/E1 substrate and NADH after 10 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 2.70nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 using [3H]-E1/E1 substrate and NADH after 10 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 3.10nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 using [3H]-E1/E1 substrate and NADH after 10 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 3.10nMAssay Description:Irreversible inhibition of STS in human T47D cells preincubated for 2 hrs followed by compound washout and addition of [3H]-E1S/E1S as substrate meas...More data for this Ligand-Target Pair Affinity DataIC50: 3.40nMAssay Description:Inhibition of STS in human T47D cells preincubated for 1 hr followed by addition of [3H]-E1S/E1S as substrate measured after 24 hrs by HPLC based rad...More data for this Ligand-Target Pair Affinity DataIC50: 3.40nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 using [3H]-E1/E1 substrate and NADH after 10 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 3.90nMAssay Description:Irreversible inhibition of STS in human T47D cells preincubated for 2 hrs followed by compound washout and addition of [3H]-E1S/E1S as substrate meas...More data for this Ligand-Target Pair Affinity DataIC50: 4.10nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD2 using [3H]-E2/E2 substrate and NAD+ after 20 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 5.10nMAssay Description:Inhibition of STS in human T47D cells preincubated for 1 hr followed by addition of [3H]-E1S/E1S as substrate measured after 24 hrs by HPLC based rad...More data for this Ligand-Target Pair Affinity DataIC50: 5.70nMAssay Description:Irreversible inhibition of STS in human T47D cells preincubated for 2 hrs followed by compound washout and addition of [3H]-E1S/E1S as substrate meas...More data for this Ligand-Target Pair Affinity DataIC50: 7.10nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 using [3H]-E1/E1 substrate and NADH after 10 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 7.90nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells preincubated for 1 hr followed by addition of [3H]-E1/E1 as substrate measured after 30 mins by HPLC ba...More data for this Ligand-Target Pair Affinity DataIC50: 10nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 using [3H]-E1/E1 substrate and NADH after 10 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 12nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 using [3H]-E1/E1 substrate and NADH after 10 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 14nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD2 using [3H]-E2/E2 substrate and NAD+ after 20 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 15nMAssay Description:Inhibition of human placental microsomal STS assessed as formation of E1 preincubated for 30 mins followed by addition of E1S as substrate measured a...More data for this Ligand-Target Pair Affinity DataIC50: 16nMAssay Description:Inhibition of STS in human T47D cells preincubated for 1 hr followed by addition of [3H]-E1S/E1S as substrate measured after 24 hrs by HPLC based rad...More data for this Ligand-Target Pair Affinity DataIC50: 16nMAssay Description:Irreversible inhibition of STS in human T47D cells preincubated for 2 hrs followed by compound washout and addition of [3H]-E1S/E1S as substrate meas...More data for this Ligand-Target Pair Affinity DataIC50: 17nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD2 using [3H]-E2/E2 substrate and NAD+ after 20 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 18nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD2 using [3H]-E2/E2 substrate and NAD+ after 20 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 19nMAssay Description:Inhibition of human placental microsomal STS assessed as formation of E1 preincubated for 30 mins followed by addition of E1S as substrate measured a...More data for this Ligand-Target Pair Affinity DataIC50: 19nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD2 using [3H]-E2/E2 substrate and NAD+ after 20 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 20nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells preincubated for 1 hr followed by addition of [3H]-E1/E1 as substrate measured after 30 mins by HPLC ba...More data for this Ligand-Target Pair Affinity DataIC50: 20nMAssay Description:Inhibition of human placental microsomal STS assessed as formation of E1 preincubated for 30 mins followed by addition of E1S as substrate measured a...More data for this Ligand-Target Pair Affinity DataIC50: 22nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells preincubated for 1 hr followed by addition of [3H]-E1/E1 as substrate measured after 30 mins by HPLC ba...More data for this Ligand-Target Pair Affinity DataIC50: 22nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD2 using [3H]-E2/E2 substrate and NAD+ after 20 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 23nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 using [3H]-E1/E1 substrate and NADH after 10 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 23nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD2 using [3H]-E2/E2 substrate and NAD+ after 20 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 28nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD2 using [3H]-E2/E2 substrate and NAD+ after 20 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 31nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD2 using [3H]-E2/E2 substrate and NAD+ after 20 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 31nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD2 using [3H]-E2/E2 substrate and NAD+ after 20 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 32nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 using [3H]-E1/E1 substrate and NADH after 10 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 35nMAssay Description:Inhibition of human placental microsomal STS assessed as formation of E1 preincubated for 30 mins followed by addition of E1S as substrate measured a...More data for this Ligand-Target Pair Affinity DataIC50: 36nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD2 using [3H]-E2/E2 substrate and NAD+ after 20 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 40nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD2 using [3H]-E2/E2 substrate and NAD+ after 20 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 42nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells preincubated for 1 hr followed by addition of [3H]-E1/E1 as substrate measured after 30 mins by HPLC ba...More data for this Ligand-Target Pair Affinity DataIC50: 44nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 using [3H]-E1/E1 substrate and NADH after 10 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 61nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells preincubated for 1 hr followed by addition of [3H]-E1/E1 as substrate measured after 30 mins by HPLC ba...More data for this Ligand-Target Pair Affinity DataIC50: 71nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD2 using [3H]-E2/E2 substrate and NAD+ after 20 mins by HPLC based radio-detection methodMore data for this Ligand-Target Pair Affinity DataIC50: 82nMAssay Description:Inhibition of human placental microsomal STS assessed as formation of E1 preincubated for 30 mins followed by addition of E1S as substrate measured a...More data for this Ligand-Target Pair Affinity DataIC50: 106nMAssay Description:Inhibition of human placental microsomal STS assessed as formation of E1 preincubated for 30 mins followed by addition of E1S as substrate measured a...More data for this Ligand-Target Pair Affinity DataIC50: 123nMAssay Description:Inhibition of human placental microsomal STS assessed as formation of E1 preincubated for 30 mins followed by addition of E1S as substrate measured a...More data for this Ligand-Target Pair Affinity DataIC50: 143nMAssay Description:Inhibition of human placental microsomal STS assessed as formation of E1 preincubated for 30 mins followed by addition of E1S as substrate measured a...More data for this Ligand-Target Pair Affinity DataIC50: 221nMAssay Description:Inhibition of human placental microsomal STS assessed as formation of E1 preincubated for 30 mins followed by addition of E1S as substrate measured a...More data for this Ligand-Target Pair

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endometriosis

MeSH descriptors

17-Hydroxysteroid Dehydrogenases Breast Neoplasms Endometriosis Enzyme Inhibitors Steryl-Sulfatase 17-Hydroxysteroid Dehydrogenases 17-Hydroxysteroid Dehydrogenases Breast Neoplasms Breast Neoplasms Breast Neoplasms Cell Proliferation Cell Proliferation Endometriosis Endometriosis Enzyme Inhibitors Enzyme Inhibitors Enzyme Inhibitors Female Female Humans

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