title: Hsp90 inhibitors identified from a library of novobiocin analogues.
abstract: Novobiocin is a C-terminal inhibitor of the Hsp90 protein folding machinery, which is responsible for the conformational maturation of numerous proteins involved in cancer growth and survival. Due to novobiocin's poor inhibitory activity ( approximately 700 muM), very little attention has been paid toward the development of novobiocin analogues for Hsp90 inhibition. In this study, a parallel library of 20 novobiocin derivatives was prepared and the biological activity of each evaluated by Western blot analysis of Hsp90 client proteins. A4 was found to be a potent inhibitor of Hsp90 as determined by its ability to cause the degradation of several Hsp90 client proteins in both breast and prostate cancer cell lines. In the presence of 1 muM A4, several Hsp90 client proteins were degraded, including AKT, Her2, Hif-1alpha, and the androgen receptor.
authors.affiliation: Department of Medicinal Chemistry and The Center for Protein Structure and Function, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, Kansas 66045-7582, USA.
authors.forename: Xiao Ming
authors.initials: XM
authors.lastname: Yu
authors.forename: Gang
authors.initials: G
authors.lastname: Shen
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
authors.forename: Helen
authors.initials: H
authors.lastname: Blake
authors.forename: Jeff
authors.initials: J
authors.lastname: Holzbeierlein
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cronk
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
mesh_terms: D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D009675:Novobiocin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D017510:Protein Folding; D011944:Receptors, Androgen / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D018841:HSP90 Heat-Shock Proteins; D011944:Receptors, Androgen; D009675:Novobiocin