Faculty of Pharmacy , University of Ljubljana , 1000 Ljubljana , Slovenia.
J Med Chem. 2020 Feb 13;63(3):884-904. doi: 10.1021/acs.jmedchem.9b00726. Epub 2019 Oct 21.
Human DNA topoisomerase II is an important target in anticancer therapy. Despite the clinical success of drugs that target topoisomerase II, the development of resistant cancer cells can limit their clinical efficacy. To maximize the therapeutic potential of anticancer drugs, combination therapies and multitarget drugs have been suggested in many studies, where the use of multitarget drugs is advantageous from a pharmacokinetic point of view. There are various different options for the preparation of dual-target or multiple-target inhibitors, as topoisomerase II is both structurally (e.g., topoisomerase I, Hsp90, and kinases) and functionally (e.g., histone deacetylases and proteasome) connected to many validated anticancer targets. In this Perspective, we discuss the scientific background behind targeting topoisomerase II together with a number of other targets important in cancer therapy, review the present status, and discuss further options in the field.
人类 DNA 拓扑异构酶 II 是癌症治疗中的一个重要靶点。尽管针对拓扑异构酶 II 的药物在临床上取得了成功，但耐药癌细胞的发展可能会限制其临床疗效。为了最大限度地发挥抗癌药物的治疗潜力，许多研究提出了联合治疗和多靶点药物，从药代动力学的角度来看，使用多靶点药物具有优势。有多种不同的方法可以制备双靶点或多靶点抑制剂，因为拓扑异构酶 II 在结构上（例如拓扑异构酶 I、Hsp90 和激酶）和功能上（例如组蛋白去乙酰化酶和蛋白酶体）与许多已验证的抗癌靶点相关。在本观点中，我们讨论了靶向拓扑异构酶 II 以及癌症治疗中其他一些重要靶点的科学背景，回顾了现状，并讨论了该领域的进一步选择。
