Fragment-Based Design of Small Molecule X-Linked Inhibitor of Apoptosis Protein Inhibitors

被引：47

作者：

Huang, Jui-Wen ^{[1
]}

Zhang, Ziming ^{[1
]}

Wu, Bainan ^{[1
]}

Cellitti, Jason F. ^{[1
]}

Zhang, Xiyun ^{[1
]}

Dahl, Russell ^{[1
]}

Shiau, Chung-Wai ^{[1
]}

Welsh, Kate ^{[1
]}

Emdadi, Aras ^{[1
]}

Stebbins, John L. ^{[1
]}

Reed, John C. ^{[1
]}

Pellecchia, Maurizio ^{[1
]}

机构：

[1] Burnham Inst Med Res, La Jolla, CA 92037 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 22期

关键词：

D O I：

10.1021/jm8006992

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report on a general structure- and NMR-based approach to derive druglike small molecule inhibitors of protein-protein interactions in a rapid and efficient manner. We demonstrate the utility of the approach by deriving novel and effective SMAC mimetics targeting the antiapoptotic protein X-linked inhibitor of apoptosis protein (XIAP). The XIAP baculovirus IAP repeat 3 (Bir3) domain binds directly to the N-terminal of caspase-9, thus inhibiting programmed cell death. It has been shown that in the cell this interaction can be displaced by the protein second mitochondrial activator of caspases (SMAC) and that its N-terminal tetrapeptide region (NH2-AVPI, Ala-Val-Pro-Ile) is responsible for this activity. However, because of their limited cell permeability, synthetic SMAC peptides are inefficient when tested in cultured cells, limiting their use as potential chemical tools or drug candidates against cancer cells. Hence, as an application, we report on the derivation of novel, selective, druglike, cell permeable SMAC mimics with cellular activity.

引用

页码：7111 / 7118

页数：8

共 44 条

[1] A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL- and etoposide-induced apoptosis in breast cancer cells [J].