Structure-activity relationship for the first-in-class clinical steroid sulfatase inhibitor irosustat (STX64, BN83495)

L W. Lawrence Woo, Dharshini Ganeshapillai, Mark P. Thomas, Oliver B. Sutcliffe, Bindu Malini, Mary F. Mahon, Atul Purohit, Barry V. L. Potter

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Structure-activity relationship studies were conducted on Irosustat (STX64, BN83495), the first steroid sulfatase (STS) inhibitor to enter diverse clinical trials for patients with advanced hormone-dependent cancer. The size of its aliphatic ring was expanded; its sulfamate group was N,N-dimethylated, relocated to another position and flanked by an adjacent methoxy group; and series of quinolin-2(1H)-one and quinoline derivatives of Irosustat were explored. The STS inhibitory activities of the synthesised compounds were assessed in a preparation of JEG-3 cells. Stepwise enlargement of the aliphatic ring from 7 to 11 members increases potency, although a further increase in ring size is detrimental. The best STS inhibitors in vitro had IC(50) values between 0.015 and 0.025 nm. Other modifications made to Irosustat were found to either abolish or significantly weaken its activity. An azomethine adduct of Irosustat with N,N-dimethylformamide (DMF) was isolated, and crystal structures of Irosustat and this adduct were determined. Docking studies were conducted to explore the potential interactions between compounds and the active site of STS, and suggest a sulfamoyl group transfer to formylglycine 75 during the inactivation mechanism.
Original languageEnglish
Pages (from-to)2019-2034
Number of pages16
Issue number11
Early online date25 Aug 2011
Publication statusPublished - 4 Nov 2011


  • steroid sulfatase
  • breast cancer
  • irosustat
  • stx64
  • inhibitors
  • endocrine therapy


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