title: Structure-based discovery of a new class of Hsp90 inhibitors.
abstract: Docking-based virtual screening identified 1-(2-phenol)-2-naphthol compounds as a new class of Hsp90 inhibitors of low to sub-micromolar potency. Here we report the binding affinities and cellular activities of several members of this class. A high resolution crystal structure of the most potent compound reveals its binding mode in the ATP binding site of Hsp90, providing a rationale for the observed activity of the series and suggesting strategies for developing compounds with improved properties.
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Abington, Cambridge CB1 6GB, UK. x.barril@vernalis.com
authors.forename: Xavier
authors.initials: X
authors.lastname: Barril
authors.forename: Paul
authors.initials: P
authors.lastname: Brough
authors.forename: Martin
authors.initials: M
authors.lastname: Drysdale
authors.forename: Roderick E
authors.initials: RE
authors.lastname: Hubbard
authors.forename: Andrew
authors.initials: A
authors.lastname: Massey
authors.forename: Allan
authors.initials: A
authors.lastname: Surgenor
authors.forename: Lisa
authors.initials: L
authors.lastname: Wright
mesh_terms: D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D009284:Naphthols / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D009284:Naphthols