An Hsp90 modulator that exhibits a unique mechanistic profile.
An Hsp90 modulator that exhibits a unique mechanistic profile.
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具有独特机械特性的 Hsp90 调制器。
DOI：
10.1016/j.bmcl.2012.03.012
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发表时间：
2012
影响因子：
2.7
通讯作者：
McAlpine,ShelliR
中科院分区：
文献类型：
--
作者：
Ramsey,DeborahM;McConnell,JeanetteR;Alexander,LeslieD;Tanaka,KaishinW;Vera,ChesterM;McAlpine,ShelliR
描述了细胞毒性大环的两个生物素化衍生物的合成。下拉实验表明该大环靶向Hsp90的n -中间结构域。未标记的化合物可以有效地竞争掉标记的化合物- Hsp90蛋白复合物，证实了大环对Hsp90的结合特异性。大环与Sansalvamide A （San A）的其他结构相关类似物的效力相似，并通过caspase 3机制诱导凋亡。与其他San A衍生物不同，我们发现大环不抑制c端客户蛋白和共伴侣蛋白与Hsp90的结合，这表明它具有独特的作用机制。
Described is the synthesis of two biotinylated derivatives of a cytotoxic macrocycle. Pull-down assays indicate that this macrocycle targets the N-middle domain of Hsp90. Untagged compound can effectively compete away tagged compound–Hsp90 protein complexes, confirming the binding specificity of the macrocycle for Hsp90. The macrocycle is similar in potency to other structurally-related analogs of Sansalvamide A (San A) and induces apoptosis via a caspase 3 mechanism. Unlike other San A derivatives, we show that the macrocycle does not inhibit binding between C-terminal client proteins and co-chaperones and Hsp90, suggesting that it has a unique mechanism of action.