Dual targeting of EGFR/HER2 receptor is an attractive strategy for cancer therapy. Four series of 4-anilinoquinoline-3-carbonitrile derivatives were designed and prepared by introducing various functional groups, including a polar hydrophilic group (carboxylic acid), a heterocyclic substituent possessing polarity to some extent, and an unpolar hydrophobic phenyl portion, at the C-6 position of the quinoline skeleton. All of the prepared derivatives were screened for their inhibitory activities against EGFR /HER2 receptors and their antiproliferative activities against the SK-BR-3 and A431 cell lines. Compounds 6a, 6g and 6d exhibited significant activities against the target cell lines. In particular, the antiproliferative activity of 6d (IC₅₀ =1.930 μM) against SK-BR-3 was over 2-fold higher than that of neratinib (IC₅₀=3.966 μM), and comparable to that of Lapatinib (IC₅₀=2.737 μM). On the other hand, 6d (IC₅₀=1.893 μM) was more active than the reference drug Neratinib (IC₅₀=2.151 μM), and showed comparable potency to Lapatinib (IC₅₀=1.285μM) against A431. Cell cycle analysis and apoptosis assays indicated that 6d arrests the cell cycle in the S phase, and it is a potent apoptotic inducer. Moreover, molecular docking exhibited the binding modes of compound 6d in EGFR and HER2 binding sites, respectively. Compound 6d can be considered as a candidate for further investigation as a more potent anticancer agent.

EGFR/HER2 受体的双重靶向是一种有吸引力的癌症治疗策略。通过在C端引入极性亲水基团（羧酸）、具有一定极性的杂环取代基和非极性疏水苯基部分，设计并制备了四个系列的4-苯胺喹啉-3-腈衍生物。 -6 喹啉骨架的位置。筛选所有制备的衍生物对EGFR/HER2受体的抑制活性和对SK-BR-3和A431细胞系的抗增殖活性。化合物6a、6g和6d对靶细胞系表现出显着的活性。尤其是6d (IC ₅₀=1.930 μM) 比来那替尼 (IC ₅₀ =3.966 μM)高 2 倍以上，与拉帕替尼 (IC ₅₀ =2.737 μM)相当。在另一方面，图6d（IC ₅₀ = 1.893μM）比参考药物来那替尼（IC多种活性₅₀ = 2.151μM），并显示出相当的效力拉帕替尼（IC ₅₀ =1.285μM）对A431。细胞周期分析和细胞凋亡试验表明，6d 将细胞周期阻滞在 S 期，它是一种有效的凋亡诱导剂。此外，分子对接分别在 EGFR 和 HER2 结合位点表现出化合物6d的结合模式。化合物6d 可以考虑作为更有效的抗癌剂进行进一步研究。