title: Discovery of highly potent, nonsteroidal 17β-hydroxysteroid dehydrogenase type 1 inhibitors by virtual high-throughput screening.
abstract: 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the formation of the potent proliferation-stimulating hormone estradiol, and it is thus involved in the development of hormone-dependent breast cancer. Due to its high substrate specificity and the known relationships between its overexpression and disease incidence, 17β-HSD1 is considered an attractive target for drug development. Here, we have used structure-based virtual high-throughput screening to successfully identify potent nonsteroidal 17β-HSD1 inhibitors. Computational screening of a drug-like database containing 13 million compounds identified hits with a 2-benzylidenebenzofuran-3(2H)-one scaffold that we show to be highly potent 17β-HSD1 inhibitors. The most potent in the series, compound 1, showed an IC(50) of 45nM in our 17β-HSD1 inhibition assay, and also showed good selectivity for 17β-HSD1 over 17β-HSD2.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Štefan
authors.initials: Š
authors.lastname: Starčević
authors.forename: Samo
authors.initials: S
authors.lastname: Turk
authors.forename: Boris
authors.initials: B
authors.lastname: Brus
authors.forename: Jožko
authors.initials: J
authors.lastname: Cesar
authors.forename: Tea
authors.initials: T
authors.lastname: Lanišnik Rižner
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular
chemical_list: D004791:Enzyme Inhibitors; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human