2-substituted 4-aminoquinazoline derivatives as potential dual inhibitors of EGFR and HER2: an in silico and in vitro study

Epidermal Growth Factor Receptor (EGFR), and Human EGFR-related Receptor 2 (HER2) are validated targets for anticancer drugs which provide synergistic effects when targeted simultaneously. In the previous in silico study, ZINC21942954 which is a 2-substituted 4-aminoquinazoline derivative containing 1,3,4-oxadiazole scaffold was discovered to inhibit EGFR. Therefore, in this study, the potential of ZINC21942954 and its derivatives as dual EGFR and HER2 inhibitors was explored through a structural similarity search. This search was conducted by investigating the molecular docking and dynamics of both EFGR and HER2. Based on the result, ZINC21942954 and three other derivative compounds, namely ZINC35560729, ZINC35372090, and ZINC35560766 were selected for further in vitro inhibitory activity testing. This corresponded with the result of the in silico studies carried out, and showed that the inhibitory activity of the derivative compounds at a concentration of 1 µM, was better than that of ZINC21942954. Meanwhile, among the derivatives, ZINC35560729 showed the best results against EGFR and HER2 with IC 50 values of 5.02 µM and 0.83 µM, respectively. This derivative was also selective in targeting EGFR and HER2. Therefore, it can be used as a lead compound in the further development of anticancer agents. Graphical abstract