Discovery of as a highly potent, selective ATR inhibitor for the treatment of FLT3-mutated acute myeloid leukemia.

Ataxia telangiectasia mutated and RAD3-related (ATR) kinase supports cancer cell survival managing DNA damage or replication stress in various cancers, including acute myeloid leukemia (AML). Pharmacological inhibition of ATR has emerged as a promising therapeutic strategy through synthetic lethality, particularly in contexts involving specific DNA damage response deficiencies or in combination with other agents. Herein, we report an efficient and selective ATR inhibitor, , which was developed a ring-opening strategy. Furthermore, we demonstrate its potential as a ligand for prodrugs or PROTACs. Additionally, we identify FLT3 as its potential synthetic lethal target. Compared with FLT3-wild-type acute myeloid leukemia (AML), , along with other tested ATR inhibitors, more effectively inhibits cell proliferation in FLT3-mutated AML. Moreover, potently disrupts the cell cycle and induces apoptosis in MV-4-11 cells. In addition, when combined with clinically approved FLT3 inhibitors, exhibits synergistic anti-AML effects. Therefore, our findings introduce a promising ATR inhibitor and propose the combination of ATR and FLT3 inhibition as a novel synthetic lethal strategy for treating FLT3-mutated AML.