Steroid Sulfatase Inhibition by Aryl Sulfamates: Clinical Progress, Mechanism and Future Prospects.
Steroid sulfatase is an emerging drug target for the endocrine therapy of hormone-dependent diseases, catalyzing estrogen sulfate hydrolysis to estrogen. Drug discovery, developing the core aryl O-sulfamate pharmacophore, has led to steroidal and non-steroidal drugs entering numerous clinical trials, with promising results in oncology and women's health. Steroidal estrogen sulfamate derivatives were the first irreversible active-site-directed inhibitors and one was developed clinically as an oral estradiol pro-drug and for endometriosis applications. This review summarizes work leading to the therapeutic concept of sulfatase inhibition, clinical trials executed to date and new insights into the mechanism of inhibition of steroid sulfatase. To date the non-steroidal sulfatase 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 sulfamoyl 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 Pseudomonas aeruginosa arylsulfatase enzyme suggest two possible sulfamate-based adducts with active site hydrated formylglycine as candidates for the inhibition end product via sulfamoyl group transfer, and a speculative choice is suggested. The clinical status of sulfatase inhibition is surveyed and how it might develop in the future. Also discussed are dual-targeting approaches, development of 2-substituted steroidal sulfamates and nonsteroidal derivatives as multi-targeting agents for hormone-independent tumours with other emerging directions.