Design and Optimization of Novel Benzimidazole- and Imidazo[4,5-b]pyridine-Based ATM Kinase Inhibitors with Subnanomolar Activities

The ATM kinase is a promising target in cancer treatmentas animportant regulator of the cellular response to DNA double-strandbreaks. In this work, we present a new class of specific benzimidazole-basedATM inhibitors with picomolar potency against the isolated enzymeand favorable selectivity within relative PIKK and PI3K kinases. Wecould identify two promising inhibitor subgroups with significantlydifferent physicochemical properties, which we developed simultaneously.These efforts lead to numerous highly active inhibitors with picomolarenzymatic activities. Furthermore, initial low cellular activitieson A549 cells could be increased significantly in numerous examplesresulting in cellular IC50 values in the subnanomolar range.Further characterization of the highly potent inhibitors 90 und 93 revealed promising pharmacokinetic propertiesand strong activities in organoids in combination with etoposide.Additionally, 93 showed no off-target activities withina kinome-representative mini kinase panel, with favorable selectivitieswithin the PIKK- and PI3K-families.