Aliagas-Martin Ignacio, Burdick Dan, Corson Laura, Dotson Jennafer, Drummond Jason, Fields Carter, Huang Oscar W, Hunsaker Thomas, Kleinheinz Tracy, Krueger Elaine, Liang Jun, Moffat John, Phillips Gail, Pulk Rebecca, Rawson Thomas E, Ultsch Mark, Walker Leslie, Wiesmann Christian, Zhang Birong, Zhu Bing-Yan, Cochran Andrea G
Department of Small Molecule Drug Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
J Med Chem. 2009 May 28;52(10):3300-7. doi: 10.1021/jm9000314.
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.
两种主要的极光激酶在不同的有丝分裂阶段发挥关键作用。这些激酶的选择性抑制剂以及泛极光抑制剂显示出抗肿瘤功效，目前正在进行临床研究。然而，极光A和极光B的ATP结合位点几乎相同，因此选择性抑制的结构基础尚不清楚。我们在此报告一类双苯胺嘧啶极光A抑制剂，在酶促试验和细胞表型试验中，对极光A的选择性均优于极光B。两种抑制剂与极光A形成复合物的晶体结构表明，极光B中一个氨基酸的差异导致其对该酶的抑制活性较差。在极光B（E161T）或极光A（T217E）中突变该残基足以改变抑制谱，这表明这种差异可能更广泛地用于实现对极光A的高选择性。
