Recent advances in small molecule ATR kinase inhibitors as anticancer agents

Ataxia telangiectasia and Rad3-related (ATR) kinase is a crucial regulator of the DNA damage response, supporting replication fork stability, enforcing cell-cycle checkpoints, and coordinating repair mechanisms. Tumor cells, which often experience oncogene-induced replication stress, rely more heavily on ATR signaling, presenting a potential therapeutic target for anticancer drug discovery and development. Over the last decade, intensive medicinal chemistry efforts have generated a broad pipeline of ATR inhibitors, including ceralasertib, elimusertib, camonsertib, berzosertib, ART0380, and gartisertib, many of which are in Phase I/II clinical trials. These compounds effectively disrupt checkpoints, induce replication catastrophe, and work synergistically with PARP inhibitors, topoisomerase poisons, platinum-based chemotherapies, radiotherapy, and immunotherapy. Although promising, challenges such as hematologic toxicities and resistance mechanisms persist. Future research aims to improve patient selection through biomarkers like replication-stress signatures, RAD51 foci tests, and liquid biopsy DNA damage markers; develop advanced modalities including brain-penetrant scaffolds, PROTAC degraders, and dual ATR/PARP or ATR/HDAC inhibitors; and optimize intermittent dosing to expand therapeutic windows. Incorporating these strategies into adaptive platform trials with pharmacodynamic markers and patient-centered outcomes will speed up translation. Overall, ATR inhibitors highlight progress in DNA damage response therapies, from understanding mechanisms to biomarker-driven clinical use, with the potential to revolutionize treatment across various cancers.