Discovery of new [1,4]dioxino[2,3-f]quinazoline-based inhibitors of EGFR including the T790M/L858R mutant.

A novel series of 2,3-dihydro-[1,4]dioxino[2,3-f]quinazoline derivatives were designed, synthesized and evaluated as reversible and noncovalent epidermal growth factor receptor (EGFR) inhibitors. Most of the compounds exhibited good potency against EGFR(wt) and some showed moderate to excellent potency against EGFR(T790M/L858R) mutant. The half-maximal inhibitory concentration (IC50) values of twenty-one compounds against EGFR(wt) were less than 50nM, and those of six compounds were less than 10nM. The IC50 values of eleven compounds against EGFR(T790M/L858R) were less than 100nM. Among these, compound b1 displayed the most potent inhibitory activity against EGFR(wt) (IC50=2.0nM) and EGFR(T790M/L858R) (IC50=6.9nM). Compounds with excellent inhibitory activities against EGFR(wt) and EGFR(T790M/L858R) kinase inhibitory activities showed good antiproliferative activities against H358 and A549 cells. Docking study was performed to position compound b1 into the EGFR active pocket to determine the probable binding conformation.