Estrone sulfonates as inhibitors of estrone sulfatase

Howarth, Nicola M.; Purohit, Atul; Reed, Michael J.; Potter, Barry V. L.

doi:10.1016/s0039-128x(96)00243-7

Cited by 37 publications

(28 citation statements)

References 16 publications

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“…The initial strategy employed for generating a lead STS inhibitor involved the replacement of the sulfate group (OSO 3 Ϫ ) of E1S with surrogates or mimics such as phosphate (199), phosphonates [-OP(ϭX)(OH)Me] (200 -203), sulfonates (-OSO 2 R) (204,205), sodium methylenesulfonate (-CH 2 SO 3…”

Section: B Reversible Inhibitorsmentioning

confidence: 99%

Steroid Sulfatase: Molecular Biology, Regulation, and Inhibition

et al. 2005

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Steroid sulfatase (STS) is responsible for the hydrolysis of aryl and alkyl steroid sulfates and therefore has a pivotal role in regulating the formation of biologically active steroids. The enzyme is widely distributed throughout the body, and its action is implicated in physiological processes and pathological conditions. The crystal structure of the enzyme has been resolved, but relatively little is known about what regulates its expression or activity. Research into the control and inhibition of this enzyme has been stimulated by its important role in supporting the growth of hormone-dependent tumors of the breast and prostate. STS is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be converted to steroids with estrogenic properties (i.e., estradiol and androstenediol) that can stimulate tumor growth. STS expression is increased in breast tumors and has prognostic significance. The role of STS in supporting tumor growth prompted the development of potent STS inhibitors. Several steroidal and nonsteroidal STS inhibitors are now available, with the irreversible type of inhibitor having a phenol sulfamate ester as its active pharmacophore. One such inhibitor, 667 COUMATE, has now entered a phase I trial in postmenopausal women with breast cancer. The skin is also an important site of STS activity, and deficiency of this enzyme is associated with X-linked ichthyosis. STS may also be involved in regulating part of the immune response and some aspects of cognitive function. The development of potent STS inhibitors will allow investigation of the role of this enzyme in physiological and pathological processes.

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Section: B Reversible Inhibitorsmentioning

confidence: 99%

Steroid Sulfatase: Molecular Biology, Regulation, and Inhibition

et al. 2005

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“…Initially, studies focused on the replacement of the sulfate group (OSO3 K ) of E 1 S with a range of surrogates or mimics such as phosphate (Anderson et al 1997), phosphonates (Duncan et al 1993, 2002, sulfonates (Li et al 1995, Howarth et al 1997, sodium methylenesulfonate (Li et al 1995), sulfonyl halides (Li et al 1993), sulfonamide, and the methylenesulfonyl group (Dibbelt et al 1994, Anderson et al 1997. The majority of these compounds were competitive inhibitors; designed to compete with E 1 S for the STS enzyme active site whilst remaining metabolically stable and not acting as a substrate.…”

Section: The Development Of Sts Inhibitors: a Brief Historymentioning

confidence: 99%

Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers

Purohit¹,

Foster²

2011

Journal of Endocrinology

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116

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Estrogens and androgens are instrumental in the maturation of many hormone-dependent cancers. Consequently, the enzymes involved in their synthesis are cancer therapy targets. One such enzyme, steroid sulfatase (STS), hydrolyses estrone sulfate, and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone respectively. These are the precursors to the formation of biologically active estradiol and androstenediol. This review focuses on three aspects of STS inhibitors: 1) chemical development, 2) biological activity, and 3) clinical trials. The aim is to discuss the importance of estrogens and androgens in many cancers, the developmental history of STS inhibitor synthesis, the potency of these compounds in vitro and in vivo and where we currently stand in regards to clinical trials for these drugs. STS inhibitors are likely to play an important future role in the treatment of hormone-dependent cancers. Novel in vivo models have been developed that allow pre-clinical testing of inhibitors and the identification of lead clinical candidates. Phase I/II clinical trials in postmenopausal women with breast cancer have been completed and other trials in patients with hormone-dependent prostate and endometrial cancer are currently active. Potent STS inhibitors should become therapeutically valuable in hormone-dependent cancers and other non-oncological conditions.

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“…The first reversible inhibitors to be described were sulfate surrogates of the substrate E1S or DHEAS, such as phosphate [45], phosphonates [46,47], sulfonates [48,49], or compounds linked by a heteroatom (C, N or S) to the steroidal scaffold [50][51][52].…”

Section: Reversible Inhibitors -Non-sulfamate Based Inhibitorsmentioning

confidence: 99%

Steroid sulfatase inhibitors

Horvath¹,

Billich²

2005

Expert Opinion on Therapeutic Patents

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Steroid sulfatase (STS), a microsomal enzyme catalysing the hydrolysis of the sulfate esters of 3-hydroxy steroids, has received considerable attention as an attractive drug target. It is crucial for the local production of active oestrogens and androgens from their systemic circulating sulfated precursor, namely oestrone sulfate (E1S) and dehydroepiandrosterone sulfate (DHEAS), which are involved in the pathogenesis of a number of diseases. STS inhibitors have been proposed for the treatment of breast, endometrial and prostate cancer, and for androgen-dependent skin diseases such as alopecia, hirsutism and acne. In addition to various classes of potent irreversible arylsulfamate-based inhibitors, recently novel chemotypes of reversible inhibitors originating from high-throughput screening (HTS) were discovered. All STS inhibitors to date are in the preclinical stage, with the exception of 667COUMATE, which is presently in a Phase I clinical trial. In this review the latest patent disclosures and literature in the field of STS inhibitors are summarised.

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Estrone sulfonates as inhibitors of estrone sulfatase

Cited by 37 publications

References 16 publications

Steroid Sulfatase: Molecular Biology, Regulation, and Inhibition

Steroid Sulfatase: Molecular Biology, Regulation, and Inhibition

Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers

Steroid sulfatase inhibitors

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