STEROID ENZYMES AND CANCER The Development of Steroid Sulfatase Inhibitors for Hormone-Dependent Cancer Therapy Joanna M. Day, a Atul Purohit, a Helena J. Tutill, a Paul A. Foster, a L. W. Lawrence Woo, b Barry V. L. Potter, b and Michael J. Reed a a Endocrinology and Metabolic Medicine and Sterix Ltd., Imperial College London, St. Mary’s Hospital, London, W2 1NY, United Kingdom b Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd., University of Bath, Bath, BA2 7AY, United Kingdom Steroid sulfatase (STS) regulates the hydrolysis of steroid sulfates to their unconjugated forms. Estrone sulfate and dehydroepiandrosterone sulfate can be hydrolyzed by STS to estrone and dehydroepiandrosterone, respectively, with these steroids being the pre- cursors for the synthesis of more biologically active estrogens or androgens. A number of potent STS inhibitors have now been developed including STX64, which entered a phase I trial for the treatment of postmenopausal women with advanced metastatic hormone-dependent breast cancer. The results from this phase I trial were encouraging, suggesting that STS inhibitors may also have a role in the treatment of other hormone- dependent cancers including those of the endometrium, ovary, and prostate. In this paper the potential use of STS inhibitors to treat these hormone-dependent cancers is reviewed. In addition, results from in vitro studies show that Ishikawa endometrial cancer cells, OVCAR-3 ovarian cancer cells, and LNCaP prostate cancer cells all pos- sess significant STS activity. Furthermore, STS activity in these cells can be almost completely inhibited by STX64 or the second-generation STS inhibitor, STX213. Results from these investigations therefore suggest that STS inhibitors could have therapeutic potential for the treatment of a range of hormone-dependent cancers. Key words: steroid sulfatase (STS); sulfatase inhibitor; breast cancer; prostate cancer; ovarian cancer; endometrial cancer Introduction Steroid sulfatase (STS) has a crucial role in regulating the formation of estrogens and an- drogens, which support the development and growth of a number of hormone-dependent cancers. STS is responsible for the hydrolysis of steroid sulfates, such as estrone sulfate (E1S) and dehydroepiandrosterone sulfate (DHEAS) to estrone (E1) and dehydroepiandrosterone (DHEA). E1 and DHEA can subsequently be Address for correspondence: Professor Michael J. Reed, Endocrinology and Metabolic Medicine, Imperial College London, St. Mary’s Hospital, London, W2 1NY, UK. Voice: +44-207-886-1738; fax: +44-207-886- 1790. m.reed@imperial.ac.uk converted to the biologically active estrogen estradiol (E2), and androgen testosterone, re- spectively. Over the last decade a number of potent STS inhibitors have been developed. 1,2 Most of the potent irreversible STS inhibitors to date possess the phenol sulfamate ester struc- ture as the active pharmacophore required for potent STS inhibition. 3 As STS mRNA ex- pression is increased in breast tumors and, in contrast to aromatase mRNA expression, has prognostic significance, the initial use of STS inhibitors was directed to postmenopausal women with advanced metastatic breast can- cer. 4–7 The first STS inhibitor to be tested in humans was STX64 (also known as BN83495) in women with breast cancer. When tested at Steroid Enzymes and Cancer: Ann. N.Y. Acad. Sci. 1155: 80–87 (2009). doi: 10.1111/j.1749-6632.2008.03677.x C  2009 New York Academy of Sciences. 80