Exploration of novel dihydroquinoxalinone derivatives as EGFRL858R/T790M tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer.

[Display omitted] • A series of dihydroquinoxalinone derivatives targeting EGFRL858R/T790M were designed, synthesized and evaluated. • Compound 29 exhibited excellent kinase inhibitory activities. • Compound 29 displayed potent antiproliferative activities against H1975 cells. • Compound 29 strongly suppressed the growth of xenograft tumors. To overcome or delay the drug-resistance of first-generation epidermal growth factor receptor (EGFR) kinase inhibitors and non-selectivity toxicity mediated by second-generation inhibitors, splicing principle was employed to design and synthesize a series of Osimertinib derivatives containing dihydroquinoxalinone (8 – 30) as the novel third-generation inhibitors against double mutant L858R/T790M in EGFR. Among them, compound 29 showed excellent kinase inhibitory activity against EGFRL858R/T790M with an IC 50 value of 0.55 ± 0.02 nM and potent anti-proliferative activity against H1975 cells with an IC 50 value of 5.88 ± 0.07 nM. Moreover, the strong down-regulation effect of EGFR-mediated signaling pathways and the promotion of apoptosis in H1975 cells confirmed its potent antitumor activities. Compound 29 was also demonstrated with good ADME profile in various in vitro assays. Further in vivo studies confirmed that compound 29 could suppress the growth of xenograft tumors. These results verified that compound 29 would be a promising lead compound for targeting drug-resistant EGFR mutations. [ABSTRACT FROM AUTHOR]