Hybrid dual aromatase-steroid sulfatase inhibitors with exquisite picomolar inhibitory activity.

Abstract

Single agents against multiple drug targets are highly topical. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS), and several dual aromatase-sulfatase inhibitors (DASIs) have been recently reported. The best compounds from two leading classes of DASI, 3 and 9, are low nanomolar inhibitors. In search of a novel class of DASI, core motifs of two leading classes were combined to give a series of hybrid structures, with several compounds showing markedly improved dual inhibitory activities in the picomolar range in JEG-3 cells. Thus, DASIs 14 (IC50: aromatase, 15 pM; STS, 830 pM) and 15 (IC50: aromatase, 18 pM; STS, 130 pM) are the first examples of an exceptional new class of highly potent dual inhibitor that should encourage further development toward multitargeted therapeutic intervention in HDBC.

• Authors: L W Lawrence Woo, Christian Bubert, Atul Purohit, Barry V L Potter
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 2 Issue 3 Pg. 243-7 (Mar 10 2011) ISSN: 1948-5875 [Print] United States
• PMID: 24900302 (Publication Type: Journal Article)