Discovery of [1,2,3]Triazolo[4,5-c]quinoline Derivatives as a New Class of Ataxia-Telangiectasia Mutated Kinase Inhibitors

Ataxia-telangiectasia mutated (ATM) is an atypical serine/threonineprotein kinase which is implicated in the repair of DNA double-strandbreaks. Numerous reports have shown that ATM inhibition is an attractivetarget for radiotherapy and chemotherapy sensitization. Herein wereport a new series of ATM kinase inhibitors containing the 1H-[1,2,3]-triazolo-[4,5-c]-quinoline scaffold,which was obtained by virtual screening, structural optimization,and structure-activity relationship studies. Among the inhibitors, A011 was one of the most potent, with an IC50 valueof 1.0 nM against ATM. In colorectal cancer cells (SW620 and HCT116), A011 was able to inhibit activation of ATM signaling inducedby irinotecan (CPT-11) and ionizing radiation and thenincreased the sensitivity of colorectal cancer cells to irinotecanand ionizing radiation through increasing G2/M arrest and inducingapoptosis. In the SW620 human colorectal adenocarcinoma tumor xenograftmodel, A011 sensitized SW620 to CPT-11 byinhibiting ATM activity. Collectively, this work has identified apromising lead in the discovery of potent inhibitors against ATM.