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Design, synthesis, and evaluation of tricyclic, conformationally constrained small-molecule mimetics of second mitochondria-derived activator of caspases.

ABSTRACT: A series of tricyclic, conformationally constrained Smac mimetics have been designed, synthesized, and evaluated. The most potent compound 6 (WS-5) binds to XIAP, cIAP-1, and cIAP-2 with K(i) of 18, 1.1, and 4.2 nM, respectively. Compound 6 antagonizes XIAP in a functional assay, induces cIAP-1 degradation, inhibits cell growth with an IC(50) of 68 nM in the MDA-MB-231 cancer cell line, and effectively induces cancer cells to undergo apoptosis.

SUBMITTER: Zhang B 

PROVIDER: S-EPMC2662380 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Design, synthesis, and evaluation of tricyclic, conformationally constrained small-molecule mimetics of second mitochondria-derived activator of caspases.

Zhang Bin B   Nikolovska-Coleska Zaneta Z   Zhang Yan Y   Bai Longchuan L   Qiu Su S   Yang Chao-Yie CY   Sun Haiying H   Wang Shaomeng S   Wu Yikang Y  

Journal of medicinal chemistry 20081201 23

A series of tricyclic, conformationally constrained Smac mimetics have been designed, synthesized, and evaluated. The most potent compound 6 (WS-5) binds to XIAP, cIAP-1, and cIAP-2 with K(i) of 18, 1.1, and 4.2 nM, respectively. Compound 6 antagonizes XIAP in a functional assay, induces cIAP-1 degradation, inhibits cell growth with an IC(50) of 68 nM in the MDA-MB-231 cancer cell line, and effectively induces cancer cells to undergo apoptosis. ...[more]

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