Laboratory of Bioorganic Chemistry of Enzymes, Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation.
Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russian Federation.
Med Res Rev. 2019 Jul;39(4):1427-1441. doi: 10.1002/med.21587. Epub 2019 Apr 19.
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a DNA repair enzyme that catalyzes the hydrolysis of the phosphodiester bond in the DNA-topoisomerase 1 (Top1) covalent complex and repairs some other 3'-end DNA adducts. Currently, Tdp1 functions as an important target in cancer drug design owing to its ability to break down various DNA adducts induced by chemotherapeutics. Tdp1 inhibitors may sensitize tumor cells to the action of Top1 poisons, thereby potentiating their effects. This mini-review summarizes findings from studies reporting the combined inhibition of Top1 and Tdp1. Two different approaches have been considered for developing such drug precursors.
酪氨酰 DNA 磷酸二酯酶 1（Tdp1）是一种 DNA 修复酶，可催化 DNA-拓扑异构酶 1（Top1）共价复合物中磷酸二酯键的水解，并修复其他一些 3'-端 DNA 加合物。目前，Tdp1 作为癌症药物设计的重要靶点，因为它能够分解化疗药物诱导的各种 DNA 加合物。Tdp1 抑制剂可使肿瘤细胞对 Top1 毒物的作用敏感，从而增强其作用。这篇迷你综述总结了报道 Top1 和 Tdp1 联合抑制的研究结果。为开发这种药物前体，考虑了两种不同的方法。
