Selective aurora kinase inhibitors identified using a taxol-induced checkpoint sensitivity screen.
Selective aurora kinase inhibitors identified using a taxol-induced checkpoint sensitivity screen.
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DOI：
10.1021/cb200305u
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发表时间：
2012-01-20
影响因子：
4
通讯作者：
Gray, Nathanael
中科院分区：
文献类型：
--
作者：
Kwiatkowski, Nicholas;Deng, Xianming;Wang, Jinhua;Tan, Li;Villa, Fabrizio;Santaguida, Stefano;Huang, Hsiao-Chun;Mitchison, Tim;Musacchio, Andrea;Gray, Nathanael
Aurora激酶家族的成员在细胞周期和有丝分裂纺锤体组装的调节中起关键作用，并且已经被深入研究作为一类新的抗癌药物的潜在靶点。我们描述了一种新的高效和选择性的极光激酶抑制剂类发现使用表型细胞屏幕。优化的抑制剂显示出Aurora抑制的许多特征，包括核内复制、多倍性和癌细胞中细胞活力的丧失。在Aurora B共晶体结构的指导下，关于激酶组范围选择性的结构-活性关系导致了关键选择性决定因素的鉴定和对Aurora A具有选择性的子系列的发现。生物化学和细胞谱与公开的Aurora抑制剂（包括VX-680、AZD 1152、MLN 8054和来自Genentech的基于嘧啶的化合物）的直接比较表明，化合物1和3将成为Aurora依赖性功能的有价值的另外的药理学探针。
The members of the Aurora kinase family play critical roles in the regulation of the cell cycle and mitotic spindle assembly and have been intensively investigated as potential targets for a new class of anti-cancer drugs. We describe a new highly potent and selective class of Aurora kinase inhibitors discovered using a phenotypic cellular screen. Optimized inhibitors display many of the hallmarks of Aurora inhibition including endoreduplication, polyploidy, and loss of cell viability in cancer cells. Structure-activity relationships with respect to kinome-wide selectivity and guided by an Aurora B co-crystal structure resulted in the identification of key selectivity determinants and discovery of a sub-series with selectivity towards Aurora A. A direct comparison of biochemical and cellular profile with respect to published Aurora inhibitors including VX-680, AZD1152, MLN8054, and a pyrimidine-based compound from Genentech demonstrates that compounds 1 and 3 will become valuable additional pharmacological probes of Aurora dependent functions.
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人类TPX2是将极光-A激酶靶向纺锤体所必需的。
影响因子：
7.8
作者：
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