Abstract
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.
Highlights
The synthesis and subsequent action of oestrogens and androgens regulate many aspects of normal mammalian endocrine physiology
Oestrogens and androgens are synthesised through the conversion of androstenedione (A4) and dehydroepiandrosterone (DHEA), both of which are androgen precursor steroids made in the adrenal cortex (Figure 1)
There has only been one STS inhibitor that has reached clinical trials, Irosustat (1, known as 667 Coumate, BN83495, or STX64) [13,14]. This drug has been tested in phase I/II trials in various settings which are examined in this review, but mainly in patients with metastatic breast cancer
Summary
The synthesis and subsequent action of oestrogens and androgens regulate many aspects of normal mammalian endocrine physiology. These sex steroids play key roles in maturation, sexual development, and reproduction. A pivotal step in the synthesis and subsequent bioavailability of active oestrogens or androgens is through the action of steroid sulphatase (STS) which hydrolyses sulphated sex steroids. Over the past 30 years, the development of STS inhibitors to treat potentially many diseases has been of significant interest to many researchers. This review will explore the past, present, and future of STS inhibitor development and will in particular focus on the research by Prof. Other recent reviews on this area sufficiently cover many other groups’ significant contributions to STS inhibitor chemistry and biology [6,7,8,9]
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