Design, Synthesis, and Antitumor Activity of Potent and Selective EGFR L858R/T790M Inhibitors and Identification of a Combination Therapy to Overcome Acquired Resistance in Models of Non-small-cell Lung Cancer

Epidermal growth factor receptor (EGFR) is one of the
most studied
drug targets for the treatment of non-small-cell lung cancer (NSCLC).
Here, we report the identification, structure optimization, and structure–activity
relationship studies of quinazoline derivatives as novel selective
EGFR L858R/T790M inhibitors. The most promising compound, 28f, exhibited strong inhibitory activity against EGFR L858R/T790M (IC50 = 3.5 nM) and greater than 368-fold selectivity over EGFR
WT (IC50 = 1290 nM), a 6.7-fold improvement over osimertinib.
Furthermore, 28f effectively inhibited downstream signaling
pathways and induced apoptosis in mutant cells. In the H1975 xenograft
in vivo model, 28f exhibited a good tumor suppressive
effect. Furthermore, the combination of 28f with the
ACK1 inhibitor dasatinib produced synergistic antiproliferative efficacy
with 28f in 28f-resistant cells and in vivo.
In conclusion,28f could become a candidate drug for the
treatment of NSCLC, and the combination of 28f and dasatinib
is expected to overcome EGFR resistance.