Design, synthesis, and biological evaluation of diphenyl ether substituted quinazolin-4-amine derivatives as potent EGFR L858R/T790M/C797S inhibitors.

Epidermal growth factor receptor (EGFR) is a validated target for non-small-cell lung cancer (NSCLC). However, the treatment for EGFR-C797S mutation induced by third-generation EGFR inhibitors remains a concern. Therefore, the development of the fourth-generation EGFR inhibitors to overcome the EGFR-C797S mutation has great potential for clinical treatment. In this article, we designed and synthesized a series of diphenyl ether substituted quinazolin-4-amine derivatives that simultaneously occupy the ATP binding pocket and the allosteric site of EGFR. Among the newly synthesized compounds, 9d displayed excellent kinase activity against EGFR ^{L858R/T790M/C797S} with an IC ₅₀ value of 0.005 μM, and exhibited anti-proliferation activity in BaF3-EGFR ^{L858R/T790M/C797S} cells with the IC ₅₀ value of 0.865 μM. Furthermore, 9d could suppress phosphorylation of EGFR and induce cell apoptosis and cycle arrest at G2 phase in a dose-dependent manner in BaF3-EGFR ^{L858R/T790M/C797S} cells. More importantly, 9d displayed significant antitumor effects in BaF3-EGFR ^{L858R/T790M/C797S} xenograft mouse model (30 mg/kg, TGI = 71.14 %). All the results indicated compound 9d might be a novel fourth-generation EGFR inhibitor for further development in overcoming the EGFR-C797S resistance mutation.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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