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
Junping Pei, Guan Wang, Aoxue Wang, Chengyong Wu, Xiaoli Pan, Shuai Wen, Faqian Bu, Yumeng Zhu, Yuxi Wang, Liang Ouyang, Weimin Li
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, 28f, exhibited strong inhibitory activity against EGFR L858R/T790M (IC 50 = 3.5 nM) and greater than 368-fold selectivity over EGFR WT (IC 50 = 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.