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

Abstract

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, <b>28f</b>, 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, <b>28f</b> effectively inhibited downstream signaling pathways and induced apoptosis in mutant cells. In the H1975 xenograft in vivo model, <b>28f</b> exhibited a good tumor suppressive effect. Furthermore, the combination of <b>28f</b> with the ACK1 inhibitor dasatinib produced synergistic antiproliferative efficacy with <b>28f</b> in <b>28f</b>-resistant cells and in vivo. In conclusion,<b>28f</b> could become a candidate drug for the treatment of NSCLC, and the combination of <b>28f</b> and dasatinib is expected to overcome EGFR resistance.