Design, synthesis and biological evaluation of aminopyrimidine derivatives bearing dihydroquinoxalinone as novel EGFRL858R/T790M kinase inhibitors against non-small-cell lung cancer

Abstract The clinical responses to the EGFR kinase inhibitors in non-small cell lung cancer (NSCLC) patients are always followed by drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFRT790M are also limited by the toxicity due to the concurrent inhibition of wide-type (WT) EGFR. Here we employed splicing principle to design and synthesize a series of aminopyrimidine derivatives bearing dihydroquinoxalinone (8-15) as novel thirdgeneration inhibitors against double mutant L858R/T790M in EGFR. It’s worth noting that compound 10 presented remarkable inhibitory activity against EGFRL858R/T790M (IC50 = 15 ± 1.8 nM) and anti-proliferative effect against H1975 cells (IC50 = 166.43 ± 14.45 nM). Moreover, the obvious down-regulation effect of EGFR-mediated signaling pathways and the promotion of apoptosis in H1975 cells confirmed its potent efficacy. These results demonstrated that compound 10 deserves the further exploration.