title: Adenine derived inhibitors of the molecular chaperone HSP90-SAR explained through multiple X-ray structures.
abstract: Multiple co-crystal structures of an adenine-based series of inhibitors bound to the molecular chaperone Hsp90 have been determined. These structures explain the observed SAR for previously described compounds and new compounds, which possess up to 8-fold improved potency against the isolated enzyme. Anti-tumour cell potency and mechanism of action data is also described for the most potent compounds. These data should enable the design of more potent Hsp90 inhibitors.
authors.affiliation: RiboTargets Ltd, Granta Park, CB1 6GB, Cambridge, UK. b.dymock@ribotargets.com
authors.forename: Brian
authors.initials: B
authors.lastname: Dymock
authors.forename: Xavier
authors.initials: X
authors.lastname: Barril
authors.forename: Mandy
authors.initials: M
authors.lastname: Beswick
authors.forename: Adam
authors.initials: A
authors.lastname: Collier
authors.forename: Nicholas
authors.initials: N
authors.lastname: Davies
authors.forename: Martin
authors.initials: M
authors.lastname: Drysdale
authors.forename: Alexandra
authors.initials: A
authors.lastname: Fink
authors.forename: Christophe
authors.initials: C
authors.lastname: Fromont
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: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray / Q000379:methods; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D000225:Adenine