Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide
Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide
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DOI：
10.1021/ja0693587
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发表时间：
2007-03-07
影响因子：
15
通讯作者：
Verdine, Gregory L.
中科院分区：
文献类型：
--
作者：
Bernal, Federico;Tyler, Andrew F.;Verdine, Gregory L.
p53-hDM2蛋白相互作用是一种有效的癌症治疗靶点。我们报道了稳定的α -螺旋p53 （SAH-p53）化合物的合成，拮抗p53- hdm2相互作用。我们证明，碳氢化合物钉接赋予细胞通透性p53肽，然后能够调节转录活性。SAH-p53先导化合物通过重新激活天然p53信号通路触发hdm2过表达癌细胞的凋亡。SAH-p53是第一个通过直接调节转录途径破坏癌症的全碳氢化合物i， i+7稳定肽。
The p53-hDM2 protein interaction is a validated therapeutic target in cancer. We report the synthesis of stabilized alpha-helix of p53 (SAH-p53) compounds that antagonize the p53-hDM2 interaction. We demonstrate that hydrocarbon stapling confers cellular permeability to a p53 peptide that is then capable of modulating transcriptional activity. The lead SAH-p53 compound triggers apoptosis in hDM2-overexpressing cancer cells by reactivating the native p53 signaling pathway. SAH-p53 is the first example of an all-hydrocarbon i, i+7 stabilized peptide that subverts cancer through direct modulation of a transcriptional pathway.