Potent, Orally Bioavailable Diazabicyclic Small-Molecule Mimetics of Second Mitochondria-Derived Activator of Caspases
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- 作者：Yuefeng Peng ; Haiying Sun ; Zaneta Nikolovska-Coleska ; Su Qiu ; Chao-Yie Yang ; Jianfeng Lu ; Qian Cai ; Han Yi ; Sanmao Kang ; Dajun Yang ; Shaomeng Wang
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：December 25, 2008
- 年：2008
- 卷：51
- 期：24
- 页码：8158-8162
- 全文大小：184K
- 年卷期：v.51,no.24(December 25, 2008)
- ISSN：1520-4804
文摘
A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized, and evaluated. The most potent compound (6) binds to XIAP, cIAP-1, and cIAP-2 with Ki values of 8.4, 1.5, and 4.2 nM, respectively, directly antagonizes XIAP in a cell-free functional assay and induces cIAP-1 degradation in cancer cells. It inhibits cell growth with an IC50 value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line, and has a good oral bioavailability.