一种具有独特作用机制特征的 HSP90 调节剂。
An Hsp90 modulator that exhibits a unique mechanistic profile.
机构信息
Department of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
出版信息
Bioorg Med Chem Lett. 2012 May 1;22(9):3287-90. doi: 10.1016/j.bmcl.2012.03.012. Epub 2012 Mar 11.
Abstract
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.
摘要
描述了两种细胞毒性大环化合物的生物素化衍生物的合成。下拉实验表明，这种大环化合物靶向 Hsp90 的 N 中端结构域。未标记的化合物可以有效地与标记的化合物-Hsp90 蛋白复合物竞争，证实了大环化合物与 Hsp90 的结合特异性。该大环化合物与其他结构相关的 Sansalvamide A（San A）类似物具有相似的效力，并通过 caspase 3 机制诱导细胞凋亡。与其他 San A 衍生物不同，我们表明该大环化合物不抑制 C 端客户蛋白与共伴侣和 Hsp90 之间的结合，表明它具有独特的作用机制。
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