SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects

Abstract

Steroid sulphatase is an emerging drug target for the endocrine therapy of hormone-dependent diseases, catalysing oestrogen sulphate hydrolysis to oestrogen. Drug discovery, developing the core aryl -sulphamate pharmacophore, has led to steroidal and non-steroidal drugs entering numerous clinical trials, with promising results in oncology and women's health. Steroidal oestrogen sulphamate derivatives were the first irreversible active-site-directed inhibitors and one was developed clinically as an oral oestradiol pro-drug and for endometriosis applications. This review summarizes work leading to the therapeutic concept of sulphatase inhibition, clinical trials executed to date and new insights into the mechanism of inhibition of steroid sulphatase. To date, the non-steroidal sulphatase inhibitor Irosustat has been evaluated clinically in breast cancer, alone and in combination, in endometrial cancer and in prostate cancer. The versatile core pharmacophore both imbues attractive pharmaceutical properties and functions via three distinct mechanisms of action, as a pro-drug, an enzyme active-site-modifying motif, likely through direct sulphamoyl group transfer, and as a structural component augmenting activity, for example by enhancing interactions at the colchicine binding site of tubulin. Preliminary new structural data on the arylsulphatase enzyme suggest two possible sulphamate-based adducts with the active site formylglycine as candidates for the inhibition end product via sulphamoyl or sulphonylamine transfer, and a speculative choice is suggested. The clinical status of sulphatase inhibition is surveyed and how it might develop in the future. Also discussed are dual-targeting approaches, development of 2-substituted steroidal sulphamates and non-steroidal derivatives as multi-targeting agents for hormone-independent tumours, with other emerging directions.

Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders

“…A dual STS/17βHSD1 inhibitor has been shown to block the proliferation of cancer cells treated with E1S/E1 but not those treated with E2 alone [ 109 ], but this awaits further testing in vivo. A range of DASI drugs have been developed and tested by Barry Potter and his colleagues, with promising results in cell and animal models (reviewed in [ 110 ]), but have yet to be tested as treatment for women with EC or endometriosis.…”

Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders

“…The evidence that STS is expressed in endometrial cancers [50,103] and endometriosis [104] has prompted development of specific STS inhibitors as novel therapies. Several potent STS inhibitors have been developed [105] including STX64 which was effective in blocking synthesis in endometrial cancer cells in vitro. STX64 has been renamed as Irosustat (Ipsen) and…”

Synthesis and in vitro evaluation of piperazinyl-ureido sulfamates as steroid sulfatase inhibitors

“…Initial potent STS inhibitors were steroid-based: estrone and estradiol-based aryl sulfamate esters are known to be time and concentration dependent irreversible active-site directed inhibitors [8]. However, because of their very potent estrogenic activity in rodents they were not deemed suitable for progression as anti-tumor drug candidates, although one of them, estradiol 3-O-sulfamate ( Figure 1, E2MATE), did reach phase II human clinical trials as a prodrug of estradiol in hormone replacement therapy [9,10]. E2MATE is still being pursued as a potential drug against the hormone-dependent disease endometriosis [11][12], that was shown to have an important STS component [13].…”

“…Further development in this area led to the clinical STS inhibitor Irosustat/STX64 ( Figure 1) [2,17]. Such aryl sulfamate derivatives in particular have proved to be the most potent STS inhibitors and have reached clinical trials [9,10]. The most recent clinical reports relate to two studies, one with Irosustat in combination with an aromatase inhibitor [20] and another demonstrating the first effects of Irosustat in early breast cancer in treatment-naïve patients [21].…”