Structure-based discovery of a new class of Hsp90 inhibitors.
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.
Barril
Xavier
X
Vernalis (R&D) Ltd, Granta Park, Abington, Cambridge CB1 6GB, UK. x.barril@vernalis.com
Brough
Paul
P
Drysdale
Martin
M
Hubbard
Roderick E
RE
Massey
Andrew
A
Surgenor
Allan
A
Wright
Lisa
L
D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D009284:Naphthols / Q000737:chemistry* / Q000494:pharmacology*
D018841:HSP90 Heat-Shock Proteins; D009284:Naphthols