title: 3-(5-Chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as inhibitors of the Hsp90 molecular chaperone.
abstract: Information from X-ray crystal structures of Hsp90 inhibitors bound to the human Hsp90 molecular chaperone was used to assist in the design of 3-(5-chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as novel inhibitors of Hsp90. Accessing an extra interaction with the protein via Phe138 gave a significant increase in binding potency compared to similar analogues that do not make this interaction.
authors.affiliation: Vernalis Ltd, Granta Park, Great Abington, Cambridge CB1 6GB, UK. p.brough@vernalis.com
authors.forename: Paul A
authors.initials: PA
authors.lastname: Brough
authors.forename: Xavier
authors.initials: X
authors.lastname: Barril
authors.forename: Mandy
authors.initials: M
authors.lastname: Beswick
authors.forename: Brian W
authors.initials: BW
authors.lastname: Dymock
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Drysdale
authors.forename: Lisa
authors.initials: L
authors.lastname: Wright
authors.forename: Kate
authors.initials: K
authors.lastname: Grant
authors.forename: Andrew
authors.initials: A
authors.lastname: Massey
authors.forename: Allan
authors.initials: A
authors.lastname: Surgenor
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D010072:Oxamic Acid / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000577:Amides; D018841:HSP90 Heat-Shock Proteins; D011720:Pyrazoles; D010072:Oxamic Acid