title: Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design.
abstract: The design and synthesis of novel adenosine-derived inhibitors of HSP70, guided by modeling and X-ray crystallographic structures of these compounds in complex with HSC70/BAG-1, is described. Examples exhibited submicromolar affinity for HSP70, were highly selective over HSP90, and some displayed potency against HCT116 cells. Exposure of compound 12 to HCT116 cells caused significant reduction in cellular levels of Raf-1 and Her2 at concentrations similar to that which caused cell growth arrest.
authors.affiliation: Vernalis (R&D) Ltd., Granta Park, Great Abington, Cambridge CB21 6GB, United Kingdom. d.williamson@vernalis.com
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Williamson
authors.forename: Jenifer
authors.initials: J
authors.lastname: Borgognoni
authors.forename: Alexandra
authors.initials: A
authors.lastname: Clay
authors.forename: Zoe
authors.initials: Z
authors.lastname: Daniels
authors.forename: Pawel
authors.initials: P
authors.lastname: Dokurno
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Drysdale
authors.forename: Nicolas
authors.initials: N
authors.lastname: Foloppe
authors.forename: Geraint L
authors.initials: GL
authors.lastname: Francis
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Graham
authors.forename: Rob
authors.initials: R
authors.lastname: Howes
authors.forename: Alba T
authors.initials: AT
authors.lastname: Macias
authors.forename: James B
authors.initials: JB
authors.lastname: Murray
authors.forename: Rachel
authors.initials: R
authors.lastname: Parsons
authors.forename: Terry
authors.initials: T
authors.lastname: Shaw
authors.forename: Allan E
authors.initials: AE
authors.lastname: Surgenor
authors.forename: Lindsey
authors.initials: L
authors.lastname: Terry
authors.forename: Yikang
authors.initials: Y
authors.lastname: Wang
authors.forename: Mike
authors.initials: M
authors.lastname: Wood
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Massey
mesh_terms: D000241:Adenosine / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D016231:Fluorescence Polarization Immunoassay; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure
chemical_list: D018840:HSP70 Heat-Shock Proteins; D000241:Adenosine