title: 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.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath , Claverton Down, Bath BA2 7AY, United Kingdom.
authors.forename: L W Lawrence
authors.initials: LW
authors.lastname: Woo
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath , Claverton Down, Bath BA2 7AY, United Kingdom.
authors.forename: Christian
authors.initials: C
authors.lastname: Bubert
authors.affiliation: Endocrinology and Metabolic Medicine, Imperial College London, Faculty of Medicine, St. Mary's Hospital , London W2 1NY, United Kingdom.
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath , Claverton Down, Bath BA2 7AY, United Kingdom.
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
keywords: Hybrid; aromatase; cancer; dual inhibitors; sulfatase