Zhang Meimei, Wang Ziqiang, Su Yan, Yan Wenbo, Ouyang Yifan, Fan Yanru, Huang Yu, Yang Hao
School of Pharmacy, Ningxia Medical University, Yinchuan 750004, PR China.
Fujian Key Laboratory of Toxicant and Drug Toxicology, School of Medicine, Ningde Normal University, Ningde, Fujian 352100, People's Republic of China.
Bioorg Chem. 2025 Jan;154:108072. doi: 10.1016/j.bioorg.2024.108072. Epub 2024 Dec 16.
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme that plays a crucial role in repairing DNA lesions caused by the entrapment of DNA topoisomerase IB (TOP1)-DNA break-associated crosslinks. TDP1 inhibitors exhibit synergistic effects with TOP1 inhibitors in cancer cells, effectively overcoming resistance to TOP1 inhibitors. Therefore, this approach presents a promising strategy for reversing tumor resistance to TOP1 inhibitors. This review comprehensively outlines the structural and biological features of TDP1, the substrates involved in its catalytic hydrolysis, and its potential as a therapeutic target in oncology. Additionally, we summarize the various screening methods used to identify TDP1 inhibitors, alongside the latest advancements in TDP1 inhibitor research.
酪氨酰-DNA磷酸二酯酶1（TDP1）是一种在修复由DNA拓扑异构酶IB（TOP1）-DNA断裂相关交联捕获引起的DNA损伤中起关键作用的酶。TDP1抑制剂在癌细胞中与TOP1抑制剂表现出协同作用，有效克服对TOP1抑制剂的耐药性。因此，这种方法为逆转肿瘤对TOP1抑制剂的耐药性提供了一种有前景的策略。本综述全面概述了TDP1的结构和生物学特性、其催化水解所涉及的底物及其作为肿瘤学治疗靶点的潜力。此外，我们总结了用于鉴定TDP1抑制剂的各种筛选方法以及TDP1抑制剂研究的最新进展。
