A Class of 2,4-Bisanilinopyrimidine Aurora A Inhibitors with Unusually High Selectivity against Aurora B

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• 作者：Ignacio Aliagas-Martin ; Dan Burdick ; Laura Corson ; Jennafer Dotson ; Jason Drummond ; Carter Fields ; Oscar W. Huang ; Thomas Hunsaker ; Tracy Kleinheinz ; Elaine Krueger ; Jun Liang ; John Moffat ; Gail Phill
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：May 28, 2009
• 年：2009
• 卷：52
• 期：10
• 页码：3300-3307
• 全文大小：222K
• 年卷期：v.52,no.10(May 28, 2009)
• ISSN：1520-4804

文摘

The two major Aurora kinases carry out critical functions at distinct mitotic stages. Selective inhibitors of these kinases, as well as pan-Aurora inhibitors, show antitumor efficacy and are now under clinical investigation. However, the ATP-binding sites of Aurora A and Aurora B are virtually identical, and the structural basis for selective inhibition has therefore not been clear. We report here a class of bisanilinopyrimidine Aurora A inhibitors with excellent selectivity for Aurora A over Aurora B, both in enzymatic assays and in cellular phenotypic assays. Crystal structures of two of the inhibitors in complex with Aurora A implicate a single amino acid difference in Aurora B as responsible for poor inhibitory activity against this enzyme. Mutation of this residue in Aurora B (E161T) or Aurora A (T217E) is sufficient to swap the inhibition profile, suggesting that this difference might be exploited more generally to achieve high selectivity for Aurora A.