Hsp90 inhibitors identified from a library of novobiocin analogues
Hsp90 inhibitors identified from a library of novobiocin analogues
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DOI：
10.1021/ja0535864
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发表时间：
2005-09-21
影响因子：
15
通讯作者：
Blagg, BSJ
中科院分区：
文献类型：
--
作者：
Yu, XM;Shen, G;Blagg, BSJ
新生霉素是Hsp 90蛋白折叠机制的C-末端抑制剂，其负责参与癌症生长和存活的许多蛋白质的构象成熟。由于新生霉素的抑制活性很差（约700 μM），很少有人关注新生霉素类似物对Hsp 90抑制的开发。在这项研究中，20新生霉素衍生物的平行库制备和Hsp 90客户端蛋白的Western印迹分析的生物活性进行了评估。A4被发现是一个有效的抑制剂Hsp 90的能力，通过其导致几个Hsp 90客户端蛋白在乳腺癌和前列腺癌细胞系的降解。在1 μ MA 4存在下，几种Hsp 90客户蛋白被降解，包括AKT、Her 2、Hif-1α和雄激素受体。
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.A4was 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 μMA4, several Hsp90 client proteins were degraded,including AKT, Her2, Hif-1α, and the androgen receptor.