Identification of a lead small-molecule inhibitor of the Aurora kinases using a structure-assisted, fragment-based approach
Aurora A and Aurora B are potential targets for anticancer drug development due to their roles in tumorigenesis and disease progression. To identify small-molecule inhibitors of the Aurora kinases, we undertook a structure-based design approach that used three-dimensional structural models of the Au...
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Veröffentlicht in: | Molecular cancer therapeutics 2006-07, Vol.5 (7), p.1764-1773 |
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Sprache: | eng |
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Zusammenfassung: | Aurora A and Aurora B are potential targets for anticancer drug development due to their roles in tumorigenesis and disease
progression. To identify small-molecule inhibitors of the Aurora kinases, we undertook a structure-based design approach that
used three-dimensional structural models of the Aurora A kinase and molecular docking simulations of chemical entities. Based
on these computational methods, a new generation of inhibitors derived from quinazoline and pyrimidine-based tricyclic scaffolds
were synthesized and evaluated for Aurora A kinase inhibitory activity, which led to the identification of 4-(6,7-dimethoxy-9 H -1,3,9-triaza-fluoren-4-yl)-piperazine-1-carbothioic acid [4-(pyrimidin-2-ylsulfamoyl)-phenyl]-amide. The lead compound showed
selectivity for the Aurora kinases when it was evaluated against a panel of diverse kinases. Additionally, the compound was
evaluated in cell-based assays, showing a dose-dependent decrease in phospho-histone H3 levels and an arrest of the cell cycle
in the G 2 -M fraction. Although biological effects were observed only at relatively high concentrations, this chemical series provides
an excellent starting point for drug optimization and further development. [Mol Cancer Ther 2006;5(7):1764–72] |
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ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.MCT-05-0524 |