Targeting ATR in Cancer therapy: A drug discovery perspective.

The ataxia telangiectasia and Rad3-related (ATR) kinase plays a pivotal role in the DNA damage response (DDR), serving as a critical regulator of replication stress and genomic stability. As a central mediator of cell cycle checkpoint signaling, ATR activation enables cancer cells to survive under conditions of DNA damage, making it an attractive therapeutic target, particularly in tumors with high replication stress or DDR deficiencies. This review outlines a comprehensive overview of the biological functions of ATR, highlighting its mechanistic roles in DNA repair, cell cycle control, and cancer cell survival. It further examines the clinical-stage ATR inhibitors (ATRi) and discusses the structure-activity relationships of preclinical compounds, aiming to offer insights for developing next-generation ATRi or degraders. The emergence of ATR dual inhibitors has also injected new vitality into targeted therapy. We also present combination strategies of ATRi with other anti-tumor agents and assess their feasibility, offering a fresh perspective on the clinical application of ATRi.