The efficacy of EGFR inhibitors is frequently affected by acquired resistance. EGFR^{19D/T790M/C797S} mutation is one of the primary reasons for the emergence of resistance after treatment with the third-generation EGFR inhibitors such as AZD9291, CO1686 and Olmutinib. To overcome the resistance mutation 19D/T790M/C797S, we designed and prepared a series of indole derivatives with the terminal hydroxyl of alkyl chain to increase extra interaction with the Asp855 in the conservative DFG site. Activity evaluation, structure-activity relationship and docking analysis were also carried out. Among them, compound 12e displayed significant inhibitory activity against EGFR^{19D/T790M/C797S} (IC₅₀ = 15.3 nM) and good selectivity over EGFR WT (IC₅₀ > 1000 nM), L858R/T790M (IC₅₀, 156.6 nM) and L858R/T790M/C797S (IC₅₀, 218.3 nM) respectively. Furthermore, 12e exhibited good growth inhibition activity, induced G1 phase cell cycle arrest and apoptosis in BaF3/EGFR^{19D/T790M/C797S} cells by suppressing EGFR phosphorylation signaling pathway. In all, our study might provide a novel structural design method and lay the solid foundation for the development of the 4th generation EGFR^{19D/T790M/C797S} inhibitors.

EGFR抑制剂的功效经常受到获得性耐药的影响。EGFR ^{19D / T790M / C797S}突变是在使用第三代EGFR抑制剂（例如AZD9291，CO1686和Olmutinib）治疗后出现耐药性的主要原因之一。为了克服19D / T790M / C797S的抗性突变，我们设计并制备了一系列带有烷基末端羟基的吲哚衍生物，以增加在保守DFG位点与Asp855的额外相互作用。还进行了活性评估，构效关系和对接分析。其中，化合物12e对EGFR ^{19D / T790M / C797S}表现出显着的抑制活性（IC ₅₀  = 15.3 nM），并且对EGFR WT的选择性很好（IC₅₀  > 1000纳米），L858R / T790M（IC ₅₀，156.6纳米）和L858R / T790M / C797S（IC ₅₀分别为218.3纳米）。此外，12e通过抑制EGFR磷酸化信号通路，在BaF3 / EGFR ^{19D / T790M / C797S}细胞中表现出良好的生长抑制活性，诱导G1期细胞周期阻滞和凋亡。总之，我们的研究可能会提供一种新颖的结构设计方法，并为开发第四代EGFR ^{19D / T790M / C797S}抑制剂奠定坚实的基础。