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

被引：75

作者：

Aliagas-Martin, Ignacio ^{[2
]}

Burdick, Dan ^{[2
]}

Corson, Laura ^{[3
]}

Dotson, Jennafer ^{[2
]}

Drummond, Jason ^{[2
]}

Fields, Carter ^{[4
]}

Huang, Oscar W. ^{[1
]}

Hunsaker, Thomas ^{[3
]}

Kleinheinz, Tracy ^{[2
]}

Krueger, Elaine ^{[2
]}

Liang, Jun ^{[2
]}

Moffat, John ^{[2
]}

Phillips, Gail ^{[4
]}

Pulk, Rebecca ^{[2
]}

Rawson, Thomas E. ^{[2
]}

Ultsch, Mark ^{[1
]}

Walker, Leslie ^{[2
]}

Wiesmann, Christian ^{[1
]}

Zhang, Birong ^{[2
]}

Zhu, Bing-Yan ^{[2
]}

Cochran, Andrea G. ^{[1
]}

机构：

[1] Genentech Inc, Dept Prot Engn, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Small Mol Drug Discovery, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Cell Regulat, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 10期

基金：

美国国家卫生研究院;

关键词：

DEPENDENT KINASE-4 INHIBITORS; SPINDLE ASSEMBLY CHECKPOINT; SMALL-MOLECULE INHIBITOR; SUPPRESSES TUMOR-GROWTH; STRUCTURAL BASIS; A KINASE; CANCER; POTENT; IDENTIFICATION; AMPLIFICATION;

D O I：

10.1021/jm9000314

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：3300 / 3307

页数：8

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