title: 4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer.
abstract: Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.
authors.affiliation: Vernalis Ltd., Granta Park, Great Abington, Cambridge CB21 6GB, U.K. p.brough@ vernalis.com
authors.forename: Paul A
authors.initials: PA
authors.lastname: Brough
authors.forename: Wynne
authors.initials: W
authors.lastname: Aherne
authors.forename: Xavier
authors.initials: X
authors.lastname: Barril
authors.forename: Jenifer
authors.initials: J
authors.lastname: Borgognoni
authors.forename: Kathy
authors.initials: K
authors.lastname: Boxall
authors.forename: Julie E
authors.initials: JE
authors.lastname: Cansfield
authors.forename: Kwai-Ming J
authors.initials: KM
authors.lastname: Cheung
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
authors.forename: Nicholas G M
authors.initials: NG
authors.lastname: Davies
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Drysdale
authors.forename: Brian
authors.initials: B
authors.lastname: Dymock
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.forename: Harry
authors.initials: H
authors.lastname: Finch
authors.forename: Alexandra
authors.initials: A
authors.lastname: Fink
authors.forename: Angela
authors.initials: A
authors.lastname: Hayes
authors.forename: Robert
authors.initials: R
authors.lastname: Howes
authors.forename: Roderick E
authors.initials: RE
authors.lastname: Hubbard
authors.forename: Karen
authors.initials: K
authors.lastname: James
authors.forename: Allan M
authors.initials: AM
authors.lastname: Jordan
authors.forename: Andrea
authors.initials: A
authors.lastname: Lockie
authors.forename: Vanessa
authors.initials: V
authors.lastname: Martins
authors.forename: Andrew
authors.initials: A
authors.lastname: Massey
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Matthews
authors.forename: Edward
authors.initials: E
authors.lastname: McDonald
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Northfield
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
authors.forename: Chrisostomos
authors.initials: C
authors.lastname: Prodromou
authors.forename: Stuart
authors.initials: S
authors.lastname: Ray
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Roughley
authors.forename: Swee Y
authors.initials: SY
authors.lastname: Sharp
authors.forename: Allan
authors.initials: A
authors.lastname: Surgenor
authors.forename: D Lee
authors.initials: DL
authors.lastname: Walmsley
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: Mike
authors.initials: M
authors.lastname: Wood
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Lisa
authors.initials: L
authors.lastname: Wright
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005454:Fluorescence Polarization; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D012118:Resorcinols / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D012118:Resorcinols