Ataxia telangiectasia and Rad3-related (ATR) kinase is a key regulating protein within the DNA damage response (DDR), responsible for sensing replication stress (RS), and has been considered as a potential target for cancer therapy. Herein, we report the discovery of a series of 6,7-dihydro-5H-pyrrolo[3,4-d]-pyrimidine derivatives as a new class of ATR inhibitors. Among them, compound 5g exhibits an IC₅₀ value of 0.007 μM against ATR kinase. In vitro, 5g displays good anti-tumor activity and could significantly reduce the phosphorylation level of ATR and its downstream signaling protein. Overall, this study provides a promising lead compound for subsequent drug discovery targeting ATR kinase.

共济失调毛细血管扩张症和 Rad3 相关 (ATR) 激酶是 DNA 损伤反应 (DDR) 中的关键调节蛋白，负责感知复制压力 (RS)，并被认为是癌症治疗的潜在靶点。在此，我们报告了一系列 6,7-二氢-5 H-吡咯并[3,4- d ]-嘧啶衍生物作为一类新型 ATR 抑制剂的发现。其中，化合物5g对 ATR 激酶的 IC ₅₀值为 0.007 μM。体外, 5g具有良好的抗肿瘤活性，可显着降低 ATR 及其下游信号蛋白的磷酸化水平。总体而言，这项研究为后续针对 ATR 激酶的药物发现提供了一种有前途的先导化合物。