First dual aromatase-steroid sulfatase inhibitors |
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Authors: | Woo L W Lawrence Sutcliffe Oliver B Bubert Christian Grasso Anna Chander Surinder K Purohit Atul Reed Michael J Potter Barry V L |
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Institution: | Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd., University of Bath, Claverton Down, Bath BA2 7AY, UK. |
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Abstract: | Aromatase inhibitors in clinical use block the biosynthesis of estrogens. Hydrolysis of estrone 3-sulfate by steroid sulfatase is an important additional source of tumor estrogen, and blockade of both enzymes should provide a more effective endocrine therapy. Sulfamoylated derivatives of the aromatase inhibitor YM511 inhibited sulfatase and aromatase in JEG-3 cells with respective IC(50) values of 20-227 and 0.82-100 nM (cf. letrozole, 0.89 nM). One dual inhibitor was potent against both enzymes in vivo, validating the concept. |
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