Discovery of novel hypoxia-activated, nitroimidazole constructed multi-target kinase inhibitors on the basis of AZD9291 for the treatment of human lung cancer

Abstract

A group of 4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine derivatives containing a hypoxia-activated nitroimidazole group were designed as EGFR inhibitors. Among this series, A14 was identified as the optimal compound, exhibiting potent anti-proliferative activities against H1975 and HCC827 cells. Under hypoxic condition, the anti-proliferative activities of A14 improved by 4–6-fold (IC₅₀ < 10 nM), indicating its hypoxia-selectivity. A14′s high potency may be attributed to its inhibition against multiple kinases, including EGFR, JAK2, ROS1, FLT3, FLT4 and PDGFRα, which was confirmed by binding assays on a panel of 30 kinases. Furthermore, A14 exhibited good bio-reductive property and could bind with nucleophilic amino acids after being activated under hypoxic conditions. With its anti-proliferative activities and selectivity for hypoxia and oncogenic kinases, A14 shows promise as a multi-target kinase inhibitor for cancer therapy.