Hsp90 Inhibitors Identified from a Library of Novobiocin Analogues
- 25 August 2005
- journal article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 127 (37) , 12778-12779
- https://doi.org/10.1021/ja0535864
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 (∼700 μM), 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 μM A4, several Hsp90 client proteins were degraded, including AKT, Her2, Hif-1α, and the androgen receptor.Keywords
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