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极光激酶抑制剂:向临床应用迈进。

Aurora kinase inhibitors: progress towards the clinic.

机构信息

Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Palacky University, Puskinova 6, Olomouc, 77520, Czech Republic.

出版信息

Invest New Drugs. 2012 Dec;30(6):2411-32. doi: 10.1007/s10637-012-9798-6. Epub 2012 Feb 18.

Abstract

The Aurora kinases (serine/threonine kinases) were discovered in 1995 during studies of mutant alleles associated with abnormal spindle pole formation in Drosophila melanogaster. They soon became the focus of much attention because of their importance in human biology and association with cancer. Aurora kinases are essential for cell division and are primarily active during mitosis. Following their identification as potential targets for cancer chemotherapy, many Aurora kinase inhibitors have been discovered, and are currently under development. The binding modes of Aurora kinase inhibitors to Aurora kinases share specific hydrogen bonds between the inhibitor core and the back bone of the kinase hinge region, while others parts of the molecules may point to different parts of the active site via noncovalent interactions. Currently there are about 30 Aurora kinase inhibitors in different stages of pre-clinical and clinical development. This review summarizes the characteristics and status of Aurora kinase inhibitors in preclinical, Phase I, and Phase II clinical studies, with particular emphasis on the mechanisms of action and resistance to these promising anticancer agents. We also discuss the validity of Aurora kinases as oncology targets, on/off-target toxicities, and other important aspects of overall clinical performance and future of Aurora kinase inhibitors.

摘要

极光激酶(丝氨酸/苏氨酸激酶)于 1995 年在研究与黑腹果蝇异常纺锤体极形成相关的突变等位基因时被发现。由于它们在人类生物学中的重要性及其与癌症的关联,它们很快成为了关注的焦点。极光激酶对于细胞分裂是必需的,并且主要在有丝分裂期间活跃。在将它们确定为癌症化疗的潜在靶标之后,已经发现了许多极光激酶抑制剂,并且目前正在开发中。极光激酶抑制剂与极光激酶的结合模式在抑制剂核心和激酶铰链区域的骨干之间共享特定的氢键,而分子的其他部分可能通过非共价相互作用指向活性位点的不同部分。目前,大约有 30 种处于不同临床前和临床开发阶段的极光激酶抑制剂。这篇综述总结了极光激酶抑制剂在临床前、I 期和 II 期临床研究中的特征和地位,特别强调了这些有前途的抗癌药物的作用机制和耐药性。我们还讨论了极光激酶作为肿瘤学靶标的有效性、脱靶毒性和整体临床性能及未来的其他重要方面。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f85b/3484309/36933d222343/10637_2012_9798_Fig1_HTML.jpg

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