title: Design, synthesis, and biological evaluation of HSP90 inhibitors based on conformational analysis of radicicol and its analogues.
abstract: The molecular chaperone HSP90 is an attractive target for chemotherapy because its activity is required for the functional maturation of a number of oncogenes. Among the known inhibitors, radicicol, a 14-member macrolide, stands out as the most potent. A molecular dynamics/minimization of radicicol showed that there were three low energy conformers of the macrocycle. The lowest of these is the bioactive conformation observed in the cocrystal structure of radicicol with HSP90. Corresponding conformational analyses of several known analogues gave a good correlation between the bioactivity and the energy of the bioactive conformer, relative to other conformers. Based on this observation, a number of proposed analogues were analyzed for their propensity to adopt the bioactive conformation prior to synthesis. This led to the identification of pochonin D, a recently isolated secondary metabolite of Pochonia chlamydosporia, as a potential inhibitor of HSP90. Pochonin D was synthesized using polymer-bound reagents and shown to be nearly as potent an HSP90 inhibitor as radicicol.
authors.affiliation: Organic and Bioorganic Chemistry Laboratory, Institut de Science et Ingénierie Supramoleculaires, Université Louis Pasteur, 8 allée Gaspard Monge, 67000 Strasbourg, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Moulin
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.forename: Sofia
authors.initials: S
authors.lastname: Barluenga
authors.forename: Martin
authors.initials: M
authors.lastname: Karplus
authors.forename: Nicolas
authors.initials: N
authors.lastname: Winssinger
mesh_terms: D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology*; D018942:Macrolides / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation
chemical_list: D018841:HSP90 Heat-Shock Proteins; D007783:Lactones; D018942:Macrolides; C502130:pochonin D; C035359:monorden