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Potent, orally bioavailable diazabicyclic small-molecule mimetics of second mitochondria-derived activator of caspases.

ABSTRACT: 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 K(i) 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 IC(50) value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line, and has a good oral bioavailability.

SUBMITTER: Peng Y 

PROVIDER: S-EPMC2679375 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Potent, orally bioavailable diazabicyclic small-molecule mimetics of second mitochondria-derived activator of caspases.

Peng Yuefeng Y   Sun Haiying H   Nikolovska-Coleska Zaneta Z   Qiu Su S   Yang Chao-Yie CY   Lu Jianfeng J   Cai Qian Q   Yi Han H   Kang Sanmao S   Yang Dajun D   Wang Shaomeng S  

Journal of medicinal chemistry 20081201 24

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 K(i) 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 IC(50) value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line, and has a good oral bio  ...[more]

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