ATR inhibitors: from targeting the DNA damage response to exploiting synthetic lethality-A paradigm shift in Cancer therapy.

Ataxia Telangiectasia and Rad3-related (ATR) kinase is a central orchestrator of the DNA replication stress response and a primary target for exploiting synthetic lethality in DDR-deficient cancers. This review systematically explores the molecular biology of ATR and the medicinal chemistry evolution of its inhibitors. We provide a detailed analysis of the structure-activity relationships (SAR) of leading clinical candidates, including berzosertib, ceralasertib, and elimusertib, focusing on strategic chemical modifications such as scaffold hopping and sulfoximine substitution to optimize selectivity and druggability. Furthermore, we critically examine the pharmacological limitations and developability hurdles associated with Proteolysis-Targeting Chimeras (PROTACs), while evaluating the progress of rational combination regimens in clinical trials. Critical challenges, specifically dose-limiting hematological toxicities and acquired resistance, are analyzed alongside the search for robust predictive biomarkers. By synthesizing current pharmacological and clinical data, this work outlines the trajectory for next-generation ATR-targeted precision medicine.