Steroid sulfatase (STS) is a new drug target for the potential treatment of a range of hormone-dependent oncology and gynecological diseases such as breast cancer and endometriosis. A collaborative research effort led by Barry Potter, University of Bath, UK, has revealed an important class of targeted yet irreversible STS inhibitors.

Irosustat is an orally active tricyclic compound and a “first-in-class” STS inhibitor, which was developed by Potter and colleagues (see picture). It is currently undergoing human clinical trials; it shows good progress thus far and an excellent safety profile. The team generated a series of Irosustat derivatives and explored the structure–activity relationship of this clinical drug as well as its potential interactions with the target enzyme. The manner by which these compounds block STS activity is thought to involve a “suicidal” sulfamoyl group transfer to an essential amino acid within the enzyme’s active site.

Although several congeners with greater potency were identified, Irosustat remains a well-established clinical drug with an overall profile that will be hard to surpass by other emerging STS inhibitors.

• Structure–Activity Relationship for the First-in-Class Clinical Steroid Sulfatase Inhibitor Irosustat (STX64, BN83495)
  L. W. L. Woo, D. Ganeshapillai, M. P. Thomas, O. B. Sutcliffe, B. Malini, M. F. Mahon, A. Purohit, B. V. L. Potter,
  ChemMedChem 2011, 6(11).
  DOI: 10.1002/cmdc.201100288