Dual aromatase-steroid sulfatase inhibitors

L.W.L. Woo, C. Bubert, O.B. Sutcliffe, A. Smith, S.K. Chander, M.F. Mahon, A. Purohit, M.J. Reed, B.V.L. Potter

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By introducting the steroid sulfatase inhibitory pharmacophore into aromatase inhibitor 1 (YM511), two series of single agent dual aromatase-sulfatase inhibitors (DASIs) were generated. The best DASIs in vitro (JEG-3 cells) are 5, (IC50(aromatase) = 0.82 nM; IC50(sulfatase) = 39 nM), and 14, (IC50(aromatase) = 0.77 nM; IC50(sulfatase) = 590 nM). X-ray crystallography of 5, and docking studies of selected compounds into an aromatase homology model and the steroid sulfatase crystal structure are presented. Both 5 and 14 inhibit aromatase and sulfatase in PMSG pretreated adult female Wistar rats potently 3 h after a single oral 10 mg/kg dose. Almost complete dual inhibition is observed for 5 but the levels were reduced to 85% (aromatase) and 72% (sulfatase) after 24 h. DASI 5 did not inhibit aldosterone synthesis. The development of a potent and selective DASI should allow the therapeutic potential of dual aromatase-sulfatase inhibition in hormone-dependent breast cancer to be assessed.
Original languageEnglish
Pages (from-to)3540-3560
Number of pages20
JournalJournal of Medicinal Chemistry
Issue number15
Publication statusPublished - 2007


  • cancer treatment research
  • chemistry
  • drugs

Cite this

Woo, L. W. L., Bubert, C., Sutcliffe, O. B., Smith, A., Chander, S. K., Mahon, M. F., Purohit, A., Reed, M. J., & Potter, B. V. L. (2007). Dual aromatase-steroid sulfatase inhibitors. Journal of Medicinal Chemistry, 50(15), 3540-3560. https://doi.org/10.1021/jm061462b