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

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.