A medicinal chemistry perspective on ATR: Current status and future directions

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-06-02 DOI:10.1016/j.ejmech.2025.117834

Kun Li , Xiangxi Sun , Shengyu Liu , Yidong Liu , Xue Feng , Guogang Zhang

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引用次数: 0

Abstract

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.

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ATR的药物化学观点：现状与未来方向

ATR（共济失调毛细血管扩张和rad3相关）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ATR抑制剂的“合成致死性”机制及其放射致敏/化学致敏特性，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，在癌症治疗中显示出良好的潜力。然而，ATR抑制剂在不同癌症中的临床疗效和安全性仍然是不容忽视的问题。本文就ATR的蛋白结构、生物学功能及其在联合治疗中的作用机制作一综述。我们重点介绍了ATR抑制剂的设计策略、结构-活性关系和生物活性评估。最后，本文将对atr靶向药物发现领域的发展进行综述，为未来的药物开发提供有价值的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.