Steroid sulfatase inhibitors: the current landscape

Anbar, Hanan S.; Isa, Zahraa; Elounais, Jana J; Jameel, Mariam A; Zib, Joudi H; Samer, Aya M; Jawad, Aya F; El–Gamal, Mohammed I.

doi:10.1080/13543776.2021.1910237

Cited by 23 publications

(16 citation statements)

References 107 publications

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“…To investigate the inhibitory activity of STS inhibitors against GSSs, virtual screening was used to dock GSS1 with 23 STS inhibitors from a review article by Anbar et al 39 The virtual screening was performed with YASARA software, and the chemical structure of ligands was merged into a file by Open Babel GUI software. We choose GSS1 as a receptor for virtual screening because of the broad activity range.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Inhibitor of Glucosinolate Sulfatases as a Potential Friendly Insecticide to Control Plutella xylostella

Wen

et al. 2022

J. Agric. Food Chem.

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The glucosinolate−myrosinase system is a two-component defense system characteristic of cruciferous plants. To evade the glucosinolate−myrosinase system, the crucifer specialist insect, Plutella xylostella, promptly desulfates the glucosinolates into harmless compounds by glucosinolate sulfatases (GSSs) in the gut. In this study, we identified an effective inhibitor of GSSs by virtual screening, molecular docking analysis, and in vitro enzyme inhibition assay. The combined effect of the GSS inhibitor with the plant glucosinolate−myrosinase system was assessed by the bioassay of P. xylostella. We show that irosustat is a GSS inhibitor and the inhibition of GSSs impairs the ability of P. xylostella to detoxify the glucosinolate−myrosinase system, leading to the systematic accumulation of toxic isothiocyanates in larvae, thereby severely affecting feeding, growth, survival, and reproduction of P. xylostella. While fed on the Arabidopsis mutants deficient in myrosinase or glucosinolates, irosustat had no significant negative effect on P. xylostella. These findings reveal that the GSS inhibitor is a novel friendly insecticide to control P. xylostella utilizing the plant glucosinolate−myrosinase system and promote the development of insecticide-plant chemical defense combination strategies.

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Section: ■ Materials and Methodsmentioning

confidence: 99%

Inhibitor of Glucosinolate Sulfatases as a Potential Friendly Insecticide to Control Plutella xylostella

Wen

et al. 2022

J. Agric. Food Chem.

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“… 8 Recent evidence prompted STS as an extremely important new molecular target in the development of novel and effective cancer therapies. 9 STS inhibition may also be of relevance in the treatment of other hormone-dependent types of tumors, for example, endometrial and prostate cancers. 10 …”

Section: Introductionmentioning

confidence: 99%

“…It acts by hydrolyzing inactive steroid sulfates [including estrone-3-sulfate (E1S) and dehydroepiandrosterone-3-sulfate (DHEAS)], , which are the precursors for the biosynthesis of active estrogens and androgens . Recent evidence prompted STS as an extremely important new molecular target in the development of novel and effective cancer therapies . STS inhibition may also be of relevance in the treatment of other hormone-dependent types of tumors, for example, endometrial and prostate cancers …”

Section: Introductionmentioning

confidence: 99%

“…As a result, in the last few decades, scientists have been intensively dedicated to finding novel and effective STS inhibitors. The latter can be basically divided into steroidal and nonsteroidal derivatives. , Among the steroidal STS inhibitors, EMATE (Figure ) stood out as the most promising compound, exhibiting a great inhibitory effect with an IC 50 value of 65 pM upon evaluation in MCF-7 cells . However, in some cases, the presence of the steroidal core resulted to be associated with the induction of side effects that limit clinical use, which include the estrogenic properties of metabolites leading to stimulation of tumor growth.…”

Section: Introductionmentioning

confidence: 99%

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Development of Sulfamoylated 4-(1-Phenyl-1H-1,2,3-triazol-4-yl)phenol Derivatives as Potent Steroid Sulfatase Inhibitors for Efficient Treatment of Breast Cancer

et al. 2022

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We present here the advances achieved in the development of new sulfamoylated 4-(1-phenyl-1 H -1,2,3-triazol-4-yl)phenol derivatives as potent steroid sulfatase (STS) inhibitors for the treatment of breast cancer. Prompted by promising biological results and in silico analysis, the initial series of similar compounds were extended, appending a variety of m-substituents at the outer phenyl ring. The inhibition profiles of the newly synthesized compounds were evaluated using a radioisotope enzymatic assay and, together with the preceding reported derivatives, using a radioisotope assay in MCF-7 cells. The most active compound, 5l , demonstrated an extraordinary STS inhibitory potency in MCF-7 cells with an IC 50 value improved 5-fold compared to that of the reference Irosustat (0.21 vs 1.06 nM). The five most potent compounds were assessed in vivo in a 67NR mouse mammary gland cancer model, with 4b measured to induce up to 51% tumor growth inhibition at 50 mg/kg with no evidence of side effects and toxicity.

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“…It is likely that these drugs will be coupled with other ovarian function inhibitors (progestins, GnRH-agonists). Also, for STS, a number of steroidal and non-steroidal inhibitors are described. ,− …”

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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Steroid sulfatase inhibitors: the current landscape

Cited by 23 publications

References 107 publications

Inhibitor of Glucosinolate Sulfatases as a Potential Friendly Insecticide to Control Plutella xylostella

Inhibitor of Glucosinolate Sulfatases as a Potential Friendly Insecticide to Control Plutella xylostella

Development of Sulfamoylated 4-(1-Phenyl-1H-1,2,3-triazol-4-yl)phenol Derivatives as Potent Steroid Sulfatase Inhibitors for Efficient Treatment of Breast Cancer

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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