Anticancer activity evaluation of indazolyl-substituted piperidin-4-yl-aminopyrimidines

Based on our previous work, a series of indazolyl-substituted piperidin-4-yl-aminopyrimidines, which were firstly used as anti-HIV agents, were evaluated for their anticancer potency in five cancer cell lines. Notably, they exhibited excellent activities with IC50 values ranging from 2.29 to 22.89 mu M in H1975 cells, among which 6c-e displayed lower cytotoxicity to normal lung cells than gefitinib. Furthermore, the typical compound 6e, which was fourfold more potent than gefitinib in H1975 cell line, was tested for its ability to inhibit H1975 cell migration. The results revealed that 6e showed superior anti-migration activity to gefitinib. In order to investigate the cytotoxicity of 6e in H1975 cells, AO/EB staining experiment was carried out and the results indicated 6e could induce cell apoptosis in a concentration-dependent manner. It is worth noting that comparing with first-generation EGFR inhibitors this series of compounds showed better anti-mutation activity, even if they lack acrylamide moiety which is regarded as necessary for anti-mutation potency in second or third-generation inhibitors. These findings indicate that it might be a new concept to explore noncovalent and high-affinity inhibitors with excellent anti-mutation potency.