Recent progress in developing ATR inhibitors as anticancer agents

DNA damage response (DDR) pathways are crucial for ensuring the stability of the genome.The ataxia telangiectasia mutated and Rad3-related (ATR) kinase plays a central role in orchestrating the DDR, responding to DNA damage and replication stress (RS), and facilitating G2/M and S checkpoint arrest, which initiates DNA repair processes. ATR has gained attention as a potential target for cancer treatment, with numerous ATR inhibitors has been the subject of clinical research at present. ATR inhibitors demonstrate potent antitumor effects as standalone agents and exhibit synergistic effects with conventional chemotherapy, radiotherapy, immunotherapy, and other DDR inhibitors. In this review, we summarize reported ATR inhibitors and highlight the structural optimization strategies employed in their design, with a focus on structure-activity relationships, biological activity, ligand binding modes, and pharmacokinetic (PK) properties. This analysis provides valuable insights for the development of more potent and selective ATR-targeting compounds. Furthermore, we discuss recent advances in the clinical evaluation of specific ATR inhibitors and outline key challenges that remain in their future development.