Ataxia Telangiectasia and Rad3‐Related Kinase as a Drug Target and Its Inhibitors: Synthetic Aspects, Current Research and Potential Perspectives

ATR kinase is a key regulator of the DNA damage response and replication stress, with two decades of homology model-based drug design now validated by cryo-EM structures of full-length human ATR-ATRIP. This review treats ATR drug discovery as both a synthetic chemistry and structural challenge, outlining reagent-level pathways from initial hits to drug substances for clinical candidates. It includes multi-kilogram biocatalytic and photoredox-flow routes for ceralasertib, analysing the strategic logic behind each scheme, a focus absent in recent SAR-based reviews. We analyse the binding modes observed in the recent ~3 Å ATR-ATRIP inhibitor co-structures and compare them with previous PI3K homology model predictions. Additionally, we expand the discussion on selectivity to include not only the (R)-3-methylmorpholine pocket but also the aminopyrazine and macrocyclic chemotypes. The section on PROTACs is reoriented around degrading the ATR-CHK1-ATM pathway, highlighting a CHK1 degrader and ATM degrader that synergise with ATR inhibition. Finally, ATR's roles beyond oncology are considered, including neurodevelopment, mitochondrial homoeostasis, gametogenesis, and in parasitic DDR. Overall, in the current scenario, ATR inhibitors are positioned as promising candidates for repurposing in biomarker-guided therapies, balancing potency, selectivity, toxicity and resistance.