Discovery of dihydrospiro[cyclopropane-1,7′-pyrrolo[3,4-d]pyrimidine] derivatives as novel ATR inhibitors

Abstract

Ataxia telangiectasia and Rad3-related (ATR) kinase plays a critical role in the DNA damage response (DDR), making it a promising target for cancer therapy. Herein, a series of dihydrospiro[cyclopropane-1,7′-pyrrolo[3,4-d]pyrimidine] derivatives have been identified as a novel class of ATR inhibitors. Among them, compound 10h exhibited the most excellent ATR kinase inhibitory activity, with an IC₅₀ value of 6.89 nM. In vitro, 10h demonstrated potent anti-tumor activity and effectively inhibited niraparib-induced CHK1 phosphorylation in Granta-519. Pairwise drug combinational antiproliferative assays revealed that 10h and niraparib synergistically enhanced antiproliferative effects against Granta-519. These results suggested that 10h holds promise for further development as a lead compound for the design of ATR kinase-targeted therapies.