Hsp90 inhibitors identified from a library of novobiocin analogues.
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.
Yu
Xiao Ming
XM
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.
Shen
Gang
G
Neckers
Len
L
Blake
Helen
H
Holzbeierlein
Jeff
J
Cronk
Benjamin
B
Blagg
Brian S J
BS
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
D018841:HSP90 Heat-Shock Proteins; D011944:Receptors, Androgen; D009675:Novobiocin