Drugging topoisomerases: lessons and challenges.
Drugging topoisomerases: lessons and challenges.
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吸毒拓扑异构酶：课程和挑战。
DOI：
10.1021/cb300648v
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发表时间：
2013-01-18
影响因子：
4
通讯作者：
Pommier, Yves
中科院分区：
文献类型：
--
作者：
Pommier, Yves
拓扑异构酶是一种普遍存在的酶，它控制DNA的超卷曲和缠结。它们在转录和复制过程中至关重要，拓扑异构酶抑制剂是最有效和最常用的抗癌和抗菌药物之一。本综述分为两部分。在第一部分（“课程”）中，它提供了不同酶家族催化机制的背景信息（人类中有6个不同的基因，大多数细菌中有4个基因），描述了拓扑异构酶靶向药物作为拓扑异构酶毒药的“界面抑制”，并描述了临床相关的拓扑异构酶抑制剂。总结了拓扑异构酶抑制剂作用机理中发现的界面抑制原理，并讨论了拓扑异构酶抑制剂如何通过将拓扑异构酶捕获在DNA上而不是通过经典的酶抑制来杀死细胞。捕获蛋白质- dna复合物扩展到PARP抑制剂的一种新的作用机制，并可应用于转录因子的靶向。第二部分综述的重点是拓扑异构酶抑制剂的发现和精确使用所面临的挑战，包括使用化学偶联和包封选择性肿瘤递送靶向拓扑异构酶抑制剂，使用药效学生物标志物跟踪药物活性，抗癌活性反应决定因素的复杂性和患者选择。与针对酪氨酸-DNA-磷酸二酯酶1和2 （TDP1和TDP2）和PARP的DNA修复抑制剂合理联合的前景，以及开发IA型酶抑制剂的未满足需求。
Topoisomerases are ubiquitous enzymes that control DNA supercoiling and entanglements. They are essential during transcription and replication and topoisomerase inhibitors are among the most effective and most commonly used anticancer and antibacterial drugs. This review consists in two parts. In the first part (“Lessons”), it gives background information on the catalytic mechanisms of the different enzyme families (6 different genes in humans and 4 in most bacteria), describes the “interfacial inhibition” by which topoisomerase-targeted drugs act as topoisomerase poisons and describes clinically relevant topoisomerase inhibitors. It generalizes the interfacial inhibition principle, which was discovered from the mechanism of action of topoisomerase inhibitors, and discusses how topoisomerase inhibitors kill cells by trapping topoisomerases on DNA rather than by classical enzymatic inhibition. Trapping protein-DNA complexes extends to a novel mechanism of action of PARP inhibitors and could be applied to the targeting of transcription factors. The second part of the review focuses on the challenges for discovery and precise use of topoisomerase inhibitors, including targeting topoisomerase inhibitors using chemical coupling and encapsulation for selective tumor delivery, use of pharmacodynamic biomarkers to follow drug activity, complexity of the response determinants for anticancer activity and patient selection, prospects of rational combinations with DNA repair inhibitors targeting tyrosyl-DNA-phosphodiesterases 1 and 2 (TDP1 and TDP2) and PARP, and the unmeet need to develop inhibitors for type IA enzymes.
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