Li Kun, Sun Xiangxi, Liu Shengyu, Liu Yidong, Feng Xue, Zhang Guogang
Hebei University of Science & Technology, Shijiazhuang, 050018, PR China.
Hebei University of Science & Technology, Shijiazhuang, 050018, PR China; State Key Laboratory Breeding Base-Hebei Key Laboratory of Molecular Chemistry for Drug, Shijiazhuang, 050022, PR China.
Eur J Med Chem. 2025 Oct 15;296:117834. doi: 10.1016/j.ejmech.2025.117834. Epub 2025 Jun 2.
ATR (Ataxia Telangiectasia and Rad3-related) is a serine/threonine protein kinase that plays a critical role in DNA replication stress response. Based on the mechanism of "synthetic lethality" and their radiosensitizing/chemosensitizing properties, ATR inhibitors have become a popular target for drug design. Currently, several ATR inhibitors have entered clinical trials and shown promising potential in cancer treatment. However, the clinical efficacy and safety of ATR inhibitors in different cancers remain issues that cannot be overlooked. This review summarizes the protein structure and biological functions of ATR, along with its mechanisms in combination therapies. We highlight the design strategies, structure-activity relationships, and biological activity assessments of ATR inhibitors. Finally, this review endeavors to provide a comprehensive perspective on the evolving field of ATR-targeted drug discovery, offering valuable insights for future drug development.
ATR（共济失调毛细血管扩张症突变基因和Rad3相关蛋白）是一种丝氨酸/苏氨酸蛋白激酶，在DNA复制应激反应中起关键作用。基于“合成致死”机制及其放射增敏/化学增敏特性，ATR抑制剂已成为药物设计的热门靶点。目前，几种ATR抑制剂已进入临床试验，并在癌症治疗中显示出有前景的潜力。然而，ATR抑制剂在不同癌症中的临床疗效和安全性仍是不可忽视的问题。本综述总结了ATR的蛋白质结构和生物学功能，以及其在联合治疗中的机制。我们重点介绍了ATR抑制剂的设计策略、构效关系和生物活性评估。最后，本综述致力于为ATR靶向药物发现这一不断发展的领域提供全面的视角，为未来药物开发提供有价值的见解。
