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, 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.

Design, Synthesis, and Biological Evaluation of Dual Inhibitors of EGFRL858R/T790M/ACK1 to Overcome Osimertinib Resistance in Nonsmall Cell Lung Cancers

“…The GSH stability assay for compound 21a was performed based on a similar assay previously described in the literature . A total of 5 μL of a 10 mM 21a stock solution in DMSO was added to 5 μL of a 4 mM Indoprofen solution in PBS as internal standard.…”

“…The GSH stability assay for compound 21a was performed based on a similar assay previously described in the literature. 34 A total of 5 μL of a 10 mM 21a stock solution in DMSO was added to 5 μL of a 4 mM Indoprofen solution in PBS as internal standard. The mixture was diluted with PBS buffer to a total volume of 1 mL of component A. Additionally, a freshly prepared solution of 10 mM GSH in PBS buffer was used as component B.…”

“…33 In the 28f-resistant cell line derived xenografts, synergistic treatment of 28f and dasatinib significantly inhibits tumor growth. 34 Therefore, dual target of EGFR and ACK1 is a novel idea for the treatment of 28f-resistant tumors. These findings further suggest that combination therapy of ACK1 and EGFR could be a new prospective method to overcome the drug resistance of third-generation EGFR-TKIs, which provides a new possibility as drug combination therapy to cancer patients who cannot benefit from targeted monotherapy.…”

“…In addition, the combination treatment of 28f and the ACK1 inhibitor AIM-100, dasatinib, or bosutinib exerted synergistic antiproliferative efficacy in 28f -resistant cells . In the 28f -resistant cell line derived xenografts, synergistic treatment of 28f and dasatinib significantly inhibits tumor growth . Therefore, dual target of EGFR and ACK1 is a novel idea for the treatment of 28f -resistant tumors.…”