Synthesis and Biological Evaluation of Optimized Inhibitors of the Mitotic Kinesin Kif18A
Synthesis and Biological Evaluation of Optimized Inhibitors of the Mitotic Kinesin Kif18A
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DOI：
10.1021/cb500789h
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发表时间：
2015-02-01
影响因子：
4
通讯作者：
Mayer, Thomas U.
中科院分区：
文献类型：
--
作者：
Braun, Joachim;Moeckel, Martin M.;Mayer, Thomas U.
有丝分裂纺锤体是一种由微管组成的高度动态结构，介导先前复制的基因组分离到两个新生子细胞中。这一过程中的错误会导致包括肿瘤形成在内的病理学变化。有丝分裂纺锤体的形状和功能的关键是驱动蛋白，将化学能转化为机械能的分子马达蛋白。由于其快速作用模式，小分子是剖析有丝分裂过程中驱动蛋白动态功能的宝贵工具。在这项研究中，我们报告了有丝分裂驱动蛋白 Kif18A 的优化小分子抑制剂的鉴定。使用第一个确定的 Kif18A 抑制剂 BTB-1 作为先导化合物，我们合成了一系列衍生物。我们证明一些合成的衍生物有效抑制 Kif18A 的 ATP 酶活性，在低微摩尔范围内具有半最大抑制浓度 (IC50) 值。对一组 Kif18A 相关驱动蛋白的体外分析表明，与 BTB-1 相比，两种最有效的化合物显示出更高的选择性。结构-活性关系研究确定了取代基对微管聚合产生不良抑制作用。总之，我们的研究为BTB-1及其类似物的作用机制提供了关键见解，这将对高选择性和生物活性Kif18A抑制剂的进一步开发产生重大影响。由于Kif18A在实体瘤中经常过度表达，此类化合物不仅对基础研究具有极大的意义，而且有可能开辟治疗人类疾病的新策略。
The mitotic spindle, a highly dynamic structure composed of microtubules, mediates the segregation of the previously duplicated genome into the two nascent daughter cells. Errors in this process contribute to pathology including tumor formation. Key for the shape and function of the mitotic spindle are kinesins, molecular motor proteins that convert chemical energy into mechanical work. Due to their fast mode of action, small molecules are valuable tools to dissect the dynamic functions of kinesins during mitosis. In this study, we report the identification of optimized small molecule inhibitors of the mitotic kinesin Kif18A. Using BTB-1, the first identified Kif18A inhibitor, as a lead compound, we synthesized a collection of derivatives. We demonstrate that some of the synthesized derivatives potently inhibited the ATPase activity of Kif18A with a half maximal inhibitory concentration (IC50) value in the low micromolar range. In vitro analysis of a panel of Kif18A-related kinesins revealed that the two most potent compounds show improved selectivity compared to BTB-1. Structure-activity relationship studies identified substituents mediating undesired inhibitory effects on microtubule polymerization. In summary, our study provides key insights into the mechanism of action of BTB-1 and its analogs, which will have a great impact on the further development of highly selective and bioactive Kif18A inhibitors. Since Kif18A is frequently overexpressed in solid tumors, such compounds are not only of great interest for basic research but also have the potential to open up new strategies for the treatment of human diseases.