Design, Synthesis, and Evaluation of Potent, Nonpeptidic Mimetics of Second Mitochondria-Derived Activator of Caspases

A series of new Smac mimetics have been designed, synthesized, and evaluated. The most potent compound 10 binds to XIAP, cIAP-1, and cIAP-2 BIR3 proteins with K i of 3.9, 0.37, and 0.25 nM, respectively. Compound 10 antagonizes XIAP in a cell-free functional assay and induces rapid cIAP-1 degradatio...

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Veröffentlicht in:	Journal of medicinal chemistry 2009-02, Vol.52 (3), p.593-596
Hauptverfasser:	Sun, Wei, Nikolovska-Coleska, Zaneta, Qin, Dongguang, Sun, Haiying, Yang, Chao-Yie, Bai, Longchuang, Qiu, Su, Wang, You, Ma, Dawei, Wang, Shaomeng
Format:	Artikel
Sprache:	eng
Schlagworte:	Alanine - analogs & derivatives Alanine - chemical synthesis Alanine - pharmacology Antineoplastic agents Apoptosis - drug effects Biological and medical sciences Breast Neoplasms Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis Bridged Bicyclo Compounds, Heterocyclic - pharmacology Cell Line, Tumor General aspects Humans Inhibitor of Apoptosis Proteins - chemical synthesis Inhibitor of Apoptosis Proteins - chemistry Intracellular Signaling Peptides and Proteins - chemical synthesis Medical sciences Mitochondrial Proteins - chemical synthesis Pharmacology. Drug treatments X-Linked Inhibitor of Apoptosis Protein - metabolism
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Beschreibung
Zusammenfassung:	A series of new Smac mimetics have been designed, synthesized, and evaluated. The most potent compound 10 binds to XIAP, cIAP-1, and cIAP-2 BIR3 proteins with K i of 3.9, 0.37, and 0.25 nM, respectively. Compound 10 antagonizes XIAP in a cell-free functional assay and induces rapid cIAP-1 degradation in cancer cells. Compound 10 inhibits cell growth in the MDA-MB-231 cancer cell line with an IC50 of 8.9 nM.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm801101z