Rational Design of Novel pyrazolo[4,3- c ]quinoline Derivatives as Potent, Selective, and Orally Bioavailable ATM Inhibitors with Promising In Vivo Efficacy

ATM plays a pivotal role in the repair of DNA double-strand breaks, and its inhibition has been shown to sensitize colorectal cancer cells to both chemotherapy and radiotherapy, highlighting its potential as a therapeutic target in colorectal cancer. In this study, rational structural design led to the development of a series of pyrazolo[4,3- c ]quinoline derivatives, with good ATM inhibitory activity and enhanced inhibition of DNA-PK. Through systematic structural optimization aimed at improving ATM selectivity and in vitro metabolic stability, the optimized compound A36 was identified. A36 demonstrated potent subnanomolar ATM inhibition, excellent kinase selectivity, strong cellular sensitization to radiation and chemotherapeutic agents, and favorable pharmacokinetic properties ( F % = 80.5%). Moreover, in combination with irinotecan, A36 exhibited enhanced antitumor efficacy and synergistic effects in the HCT116 and SW620 colorectal cancer xenograft models, with a best TGI of 92.6 and 91.1%, respectively, positioning it as a promising candidate for combination chemotherapy in colorectal cancer treatment.