Design, synthesis, and biological evaluation of novel amino acid-Osimertinib conjugates as potential EGFR inhibitors.

In this study, a series of novel amino acid-conjugated Osimertinib scaffold derivatives were designed and synthesized as EGFR (T790M/L858R) mutations inhibitors. Notably, compound 10a potently inhibited EGFR (IC = 0.046 μM) and displayed anti-proliferative activities against mutant non-small cell lung cancer cells (H1975 IC: 1.619 μM). Furthermore, compound 10a down-regulated the phosphorylation of EGFR, ERK and AKT in a dose-dependent manner in H1975 cells. At 5 μM, 10a suppressed p-ERK and p-AKT levels to 38 % and 40 % of control in H1975 cells, respectively. Cell cycle analysis revealed that compound 10a inhibited the proliferation of cells by inducing cell cycle arrest in the G1 phase. Molecular modeling indicated that compound 10a exhibited a binding mode analogous to that of Osimertinib. Overall, these results demonstrate the potential of 10a as an anticancer agent warranting further development.