Design, Synthesis, and Biological Evaluation of Potent and Selective Inhibitors of Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase for the Efficient Treatment of Cancer

Ataxia telangiectasia mutated and Rad3-related (ATR), a vital member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, plays a critical role in the DNA damage response (DDR). Tumor cells with a loss of DDR function or defects in the ataxia telangiectasia mutated (ATM) gene are generally more dependent on ATR for survival, suggesting that ATR is an attractive anticancer drug target based on its synthetic lethality. Herein, we present a potent and highly selective ATR inhibitor, ZH-12 (IC50 = 0.0068 mu M). It showed potent antitumor activity as a single agent or in combination with cisplatin in the human colorectal adenocarcinoma LoVo tumor xenograft mouse model. Overall, ZH-12 may be a promising ATR inhibitor based on the principle of synthetic lethality and deserves further in-depth study.

Automated summary

ATR, a crucial member of the PIKK family, plays a vital role in the DNA damage response. Tumor cells with DDR dysfunction or ATM gene defects are more reliant on ATR for survival, making it an attractive anticancer drug target based on synthetic lethality. A potent and highly selective ATR inhibitor, ZH-12 (IC50 = 0.0068 mu M), demonstrated potent antitumor activity alone or in combination with cisplatin in a xenograft mouse model of human colorectal adenocarcinoma. Overall, ZH-12 appears to be a promising ATR inhibitor based on the principle of synthetic lethality and warrants further in-depth investigation.