LAUSR

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, 6 g 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 = 1.285 μM) 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.