DNA 损伤反应 (DDR) 的部署可对抗各种形式的 DNA 损伤，确保基因组稳定性。癌细胞的基因组不稳定倾向为通过抑制 DDR 通路选择性杀死癌细胞提供了治疗机会。 DNA 依赖性蛋白激酶 (DNA-PK) 是一种核丝氨酸/苏氨酸激酶，对于 DNA 双链断裂 (DSB) 修复中的非同源末端连接 (NHEJ) 途径至关重要。因此，靶向DNA-PK是一种有前景的癌症治疗策略。本文详细阐述了DNA-PK及其相关大蛋白的结构、DNA-PK抑制剂的发展历程及其临床应用的最新进展。我们重点分析基于不同支架的DNA-PK抑制剂的开发过程和构效关系（SAR）。我们希望这篇综述能为未来寻求开发新型 DNA-PK 抑制剂的研究人员提供实用信息。版权所有 © 2024 Elsevier Inc. 保留所有权利。

The deployment of DNA damage response (DDR) combats various forms of DNA damage, ensuring genomic stability. Cancer cells' propensity for genomic instability offers therapeutic opportunities to selectively kill cancer cells by suppressing the DDR pathway. DNA-dependent protein kinase (DNA-PK), a nuclear serine/threonine kinase, is crucial for the non-homologous end joining (NHEJ) pathway in the repair of DNA double-strand breaks (DSBs). Therefore, targeting DNA-PK is a promising cancer treatment strategy. This review elaborates on the structures of DNA-PK and its related large protein, as well as the development process of DNA-PK inhibitors, and recent advancements in their clinical application. We emphasize our analysis of the development process and structure-activity relationships (SARs) of DNA-PK inhibitors based on different scaffolds. We hope this review will provide practical information for researchers seeking to develop novel DNA-PK inhibitors in the future.Copyright © 2024 Elsevier Inc. All rights reserved.