Optimization of Substituted 6-Salicyl-4-Anilinoquinazoline Derivatives as Dual EGFR/HER2 Tyrosine Kinase Inhibitors

<div><p>4-Anilinoquinazolines as an important class of protein kinase inhibitor are widely investigated for epidermal growth factor receptor (EGFR) tyrosine kinase or epidermal growth factor receptor 2 (HER2) inhibition. A series of novel 6-salicyl-4-anilinoquinazoline derivatives <b>9–27</b> were prepared and evaluated for their EGFR/HER2 tyrosine kinase inhibitory activity as well as their antiproliferative properties on three variant cancer cell lines (A431, MCF-7, and A549). The bioassay results showed most of the designed compounds exhibited moderate to potent in vitro inhibitory activity in the enzymatic and cellular assays, of which compound <b>21</b> revealed the most potent dual EGFR/HER2 inhibitory activity, with IC₅₀ values of 0.12 <i>µ</i>M and 0.096 <i>µ</i>M, respectively, comparable to the control compounds Erlotinib and Lapatinib. Furthermore, the kinase selectivity profile of <b>21</b> was accessed and demonstrated its good selectivity over the majority of the close kinase targets. Docking simulation was performed to position compound <b>21</b> into the EGFR/HER2 active site to determine the probable binding pose. These new findings along with molecular docking observations could provide an important basis for further development of compound <b>21</b> as a potent EGFR/HER2 dual kinase inhibitor.</p>