Structure-based discovery of a new class of Hsp90 inhibitors

TitleStructure-based discovery of a new class of Hsp90 inhibitors
Publication TypeJournal Article
Year of Publication2005
AuthorsBarril, X, Brough P, Drysdale M, Hubbard RE, Massey A, Surgenor A, Wright L
JournalBioorganic & medicinal chemistry letters
Pagination5187 - 5191
Date Published2005/12/01/
Keywords&, Heat-Shock, HSP90, Humans;, inhibitors;, Molecular, Naphthols/chemistry/pharmacology, Proteins/antagonists, Structure;
AbstractDocking-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.