title: Combining hit identification strategies: fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone.
abstract: Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC50 = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model.
authors.affiliation: Vernalis Ltd., Granta Park, Great Abington, Cambridge CB21 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: Jenifer
authors.initials: J
authors.lastname: Borgognoni
authors.forename: Patrick
authors.initials: P
authors.lastname: Chene
authors.forename: Nicholas G M
authors.initials: NG
authors.lastname: Davies
authors.forename: Ben
authors.initials: B
authors.lastname: Davis
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: Carlos
authors.initials: C
authors.lastname: Garcia-Echeverria
authors.forename: Christophe
authors.initials: C
authors.lastname: Fromont
authors.forename: Angela
authors.initials: A
authors.lastname: Hayes
authors.forename: Roderick E
authors.initials: RE
authors.lastname: Hubbard
authors.forename: Allan M
authors.initials: AM
authors.lastname: Jordan
authors.forename: Michael Rugaard
authors.initials: MR
authors.lastname: Jensen
authors.forename: Andrew
authors.initials: A
authors.lastname: Massey
authors.forename: Angela
authors.initials: A
authors.lastname: Merrett
authors.forename: Antony
authors.initials: A
authors.lastname: Padfield
authors.forename: Rachel
authors.initials: R
authors.lastname: Parsons
authors.forename: Thomas
authors.initials: T
authors.lastname: Radimerski
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: Alan
authors.initials: A
authors.lastname: Robertson
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Roughley
authors.forename: Joseph
authors.initials: J
authors.lastname: Schoepfer
authors.forename: Heather
authors.initials: H
authors.lastname: Simmonite
authors.forename: Swee Y
authors.initials: SY
authors.lastname: Sharp
authors.forename: Allan
authors.initials: A
authors.lastname: Surgenor
authors.forename: Melanie
authors.initials: M
authors.lastname: Valenti
authors.forename: Steven
authors.initials: S
authors.lastname: Walls
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: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D005260:Female; D005454:Fluorescence Polarization; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D011743:Pyrimidines