title: Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms.
abstract: Inhibition of the ATPase activity of the chaperone protein HSP90 is a potential strategy for treatment of cancers. We have determined structures of the HSP90alpha N-terminal domain complexed with the purine-based inhibitor, PU3, and analogs with enhanced potency both in enzyme and cell-based assays. The compounds induce upregulation of HSP70 and downregulation of the known HSP90 client proteins Raf-1, CDK4, and ErbB2, confirming that the molecules inhibit cell growth by a mechanism dependent on HSP90 inhibition. We have also determined the first structure of the N-terminal domain of HSP90beta, complexed with PU3. The structures allow a detailed rationale to be developed for the observed affinity of the PU3 class of compounds for HSP90 and also provide a structural framework for design of compounds with improved binding affinity and drug-like properties.
authors.affiliation: Vernalis (R&D) Ltd., Granta Park, Abington, Cambridge CB1 6GB, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wright
authors.forename: Xavier
authors.initials: X
authors.lastname: Barril
authors.forename: Brian
authors.initials: B
authors.lastname: Dymock
authors.forename: Louisa
authors.initials: L
authors.lastname: Sheridan
authors.forename: Allan
authors.initials: A
authors.lastname: Surgenor
authors.forename: Mandy
authors.initials: M
authors.lastname: Beswick
authors.forename: Martin
authors.initials: M
authors.lastname: Drysdale
authors.forename: Adam
authors.initials: A
authors.lastname: Collier
authors.forename: Andy
authors.initials: A
authors.lastname: Massey
authors.forename: Nick
authors.initials: N
authors.lastname: Davies
authors.forename: Alex
authors.initials: A
authors.lastname: Fink
authors.forename: Christophe
authors.initials: C
authors.lastname: Fromont
authors.forename: Wynne
authors.initials: W
authors.lastname: Aherne
authors.forename: Kathy
authors.initials: K
authors.lastname: Boxall
authors.forename: Swee
authors.initials: S
authors.lastname: Sharp
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Roderick E
authors.initials: RE
authors.lastname: Hubbard
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000840:Anisoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011687:Purines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C494601:9-(n-butyl)-8-((3,4,5-trimethoxyphenyl)methyl)adenine; D000840:Anisoles; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D008024:Ligands; D020033:Protein Isoforms; D011687:Purines; D000251:Adenosine Triphosphatases; D000225:Adenine