Design, synthesis, and biological evaluation of 2-arylamino-4-(piperidin-4-yloxy)pyrimidines as potent EGFRT790M/L858R inhibitors to treat non-small cell lung cancer

Three types of 2-arylamino-4-(piperidin-4-yloxy)pyrimidines (I-III) were designed and synthesized as covalent EGFR(epidermal growth factor receptor)^T790M/L858R inhibitors by replacement of the common reported 4-(3-amino)phenoxyl moiety with 4-(4-hydroxy)piperidine-4-oxyl, and the introduction of fused-thiophene or -pyrrole on the pyrimidine core to strategically achieve conformational restriction. According to our biological evaluation, it was found that compound 9i could potently suppress EGFR^T790M/L858R kinase and H1975 cell proliferation, with IC₅₀ values of 4.902 nM and 0.6210 μM, respectively. Further study showed that 9i not only demonstrated highly selective inhibitory effects toward EGFR^T790M/L858R over wild-type EGFR (EGFR^WT), but it also had low cytotoxicity against normal HBE(human bronchial epithelial) and L-02 cells. Action mechanism studies showed that 9i effectively hindered cell migration and promoted Apoptosis by AO(Acridine Orange)/EB(Ethidium Bromide) staining. These data would provide important clues for the screening of novel covalent EGFR^T790M/L858R inhibitors for non-small cell lung Cancer (NSCLC) treatment.

2-arylaminopyrimidines; EGFR(T790M/L858R); Inhibitors; Non-small cell lung cancer.