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

Abstract

Ataxia-telangiectasia mutated (ATM) is an atypical serine/threonine protein kinase which is implicated in the repair of DNA double-strand breaks. Numerous reports have shown that ATM inhibition is an attractive target for radiotherapy and chemotherapy sensitization. Herein we report 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 value of 1.0 nM against ATM. In colorectal cancer cells (SW620 and HCT116), A011 was able to inhibit activation of ATM signaling induced by irinotecan (CPT-11) and ionizing radiation and then increased the sensitivity of colorectal cancer cells to irinotecan and ionizing radiation through increasing G2/M arrest and inducing apoptosis. In the SW620 human colorectal adenocarcinoma tumor xenograft model, A011 sensitized SW620 to CPT-11 by inhibiting ATM activity. Collectively, this work has identified a promising lead in the discovery of potent inhibitors against ATM.