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

Daśko, Mateusz; Demkowicz, Sebastian; Biernacki, Karol; Ciupak, Olga; Kozak, Witold; Masłyk, Maciej; Rachoń, Janusz

doi:10.1080/14756366.2020.1758692

Cited by 16 publications

(13 citation statements)

References 107 publications

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“…The ineffectiveness of the tested arylsulfamates towards BT4656 S1_11 is likely due to this family of sulfatases having evolved to target polar carbohydrate substrates, rendering the enzyme incompatible with the binding of aryl moieties, the hydrophobic substrates of the aryl sulfatases. Significant advances have been made in the design of inhibitors targeting steroid sulfatases involved in hormone-dependent cancers and some are in Phase II clinical trials [ 39 ]. There are, however, currently no targeted, effective inhibitors of carbohydrate sulfatases despite their emergence as novel targets for disease intervention [ 26 , 40 , 41 ].…”

Section: Resultsmentioning

confidence: 99%

Mobility shift-based electrophoresis coupled with fluorescent detection enables real-time enzyme analysis of carbohydrate sulfatase activity

Byrne

London

Eyers

et al. 2021

Biochemical Journal

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Sulfated carbohydrate metabolism is a fundamental process, which occurs in all domains of life. Carbohydrate sulfatases are enzymes that remove sulfate groups from carbohydrates and are essential to the depolymerisation of complex polysaccharides. Despite their biological importance, carbohydrate sulfatases are poorly studied and challenges remain in accurately assessing the enzymatic activity, specificity and kinetic parameters. Most notably, separation of desulfated products from sulfated substrates is currently a time-consuming process. In this paper, we describe the development of rapid capillary electrophoresis coupled to substrate fluorescence detection as a high-throughput and facile means of analysing carbohydrate sulfatase activity. The approach has utility for the determination of both kinetic and inhibition parameters and is based on existing microfluidic technology coupled to a new synthetic fluorescent 6S-GlcNAc carbohydrate substrate. Furthermore, we compare this technique, in terms of both time and resources, to high performance anion exchange chromatography and NMR-based methods, which are the two current ‘gold standards’ for enzymatic carbohydrate sulfation analysis. Our study clearly demonstrates the advantages of mobility shift assays for the quantification of near real-time carbohydrate desulfation by purified sulfatases, and will support the search for small molecule inhibitors of these disease-associated enzymes.

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Section: Resultsmentioning

confidence: 99%

Mobility shift-based electrophoresis coupled with fluorescent detection enables real-time enzyme analysis of carbohydrate sulfatase activity

Byrne

London

Eyers

et al. 2021

Biochemical Journal

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“…This review will explore the past, present, and future of STS inhibitor development and will in particular focus on the research by Prof. Barry Potter, who has been instrumental in the many successes in this field. Other recent reviews on this area sufficiently cover many other groups' significant contributions to STS inhibitor chemistry and biology [6][7][8][9]. Synthesis pathways for steroids with oestrogenic and androgenic properties.…”

Section: Introductionmentioning

confidence: 99%

Steroid Sulphatase and Its Inhibitors: Past, Present, and Future

Foster

2021

Molecules

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Steroid sulphatase (STS), involved in the hydrolysis of steroid sulphates, plays an important role in the formation of both active oestrogens and androgens. Since these steroids significantly impact the proliferation of both oestrogen- and androgen-dependent cancers, many research groups over the past 30 years have designed and developed STS inhibitors. One of the main contributors to this field has been Prof. Barry Potter, previously at the University of Bath and now at the University of Oxford. Upon Prof. Potter’s imminent retirement, this review takes a look back at the work on STS inhibitors and their contribution to our understanding of sulphate biology and as potential therapeutic agents in hormone-dependent disease. A number of potent STS inhibitors have now been developed, one of which, Irosustat (STX64, 667Coumate, BN83495), remains the only one to have completed phase I/II clinical trials against numerous indications (breast, prostate, endometrial). These studies have provided new insights into the origins of androgens and oestrogens in women and men. In addition to the therapeutic role of STS inhibition in breast and prostate cancer, there is now good evidence to suggest they may also provide benefits in patients with colorectal and ovarian cancer, and in treating endometriosis. To explore the potential of STS inhibitors further, a number of second- and third-generation inhibitors have been developed, together with single molecules that possess aromatase–STS inhibitory properties. The further development of potent STS inhibitors will allow their potential therapeutic value to be explored in a variety of hormone-dependent cancers and possibly other non-oncological conditions.

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“…Significant advances have been made in the design of inhibitors targeting steroid sulfatases involved in hormone dependent cancers and some are in Phase II clinical trials [37]. There are, however, currently no targeted, effective inhibitors of carbohydrate sulfatases despite their emergence as novel targets for disease intervention [25,38,39].…”

Section: Enzyme Inhibition Studies Using Ce-based Desulfation Detectimentioning

confidence: 99%

Mobility shift-based electrophoresis coupled with fluorescent detection enables real-time enzyme analysis of carbohydrate sulfatase activity

Byrne

London

Eyers

et al. 2020

Preprint

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Sulfated carbohydrate metabolism is a fundamental process, which occurs in all domains of life. Carbohydrate sulfatases are enzymes that remove sulfate groups from carbohydrates and are essential to the depolymerisation of complex polysaccharides. Despite their biological importance, carbohydrate sulfatases are poorly studied and challenges remain in accurately assessing the activity, specificity and kinetic parameters. Most notably, separation of desulfated products from sulfated substrates is currently a time-consuming process. In this paper, we describe the development of rapid capillary electrophoresis coupled to substrate fluorescence detection as a high-throughput and facile means of analysing carbohydrate sulfatase activity. The approach has utility for the determination of both kinetic and inhibition parameters and is based on existing microfluidic technology coupled to a new synthetic fluorescent 6S-GlcNAc carbohydrate substrate. Furthermore, we compare this technique in terms of both time and resources, to high performance anion exchange chromatography and NMR-based methods, which are the two current gold standards for enzymatic carbohydrate sulfation analysis. Our study clearly demonstrates the advantages of mobility shift assays for the quantification of near real-time carbohydrate desulfation by purified sulfatases, and could support the search for small molecule inhibitors of these disease-associated enzymes.

show abstract

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

Cited by 16 publications

References 107 publications

Mobility shift-based electrophoresis coupled with fluorescent detection enables real-time enzyme analysis of carbohydrate sulfatase activity

Mobility shift-based electrophoresis coupled with fluorescent detection enables real-time enzyme analysis of carbohydrate sulfatase activity

Steroid Sulphatase and Its Inhibitors: Past, Present, and Future

Mobility shift-based electrophoresis coupled with fluorescent detection enables real-time enzyme analysis of carbohydrate sulfatase activity

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