Abstract
The epidermal growth factor receptor (EGFR) has been considered a potential target for lung cancer therapy due to its essential role in regulating the survival and proliferation of cancer cells. Although erlotinib, a potent EGFR tyrosine kinase (EGFR-TK) inhibitor, has been used as the first-line drug for lung cancer treatment, acquired drug resistance caused by the T790M secondary mutation of EGFR-TK inevitably develops after a median response duration of 9-13 months. Thus, the search for promising compounds to effectively target EGFR-TK has become an imperative necessity. In this study, the kinase inhibitory activities of a series of sulfonylated indeno[1,2-c]quinolines (SIQs) against EGFR-TK were experimentally and theoretically investigated. Among the 23 SIQ derivatives studied, eight compounds showed enhanced EGFR-TK inhibitory activity (IC(50) values of ca. 0.6-10.2 nM) compared to the known drug erlotinib (IC(50) of ∼20 nM). In a cell-based assay in human cancer cell lines with EGFR overexpression (A549 and A431 cells), the eight selected SIQs all showed more significant cytotoxicity against A431 than A549 cells, consistent with the higher EGFR expression in A431 cells. Molecular docking and FMO-RIMP2/PCM calculations revealed that SIQ17 occupies the ATP-binding site of EGFR-TK, where its sulfonyl group is mainly stabilized by C797, L718, and E762 residues. Triplicate 500 ns molecular dynamics (MD) simulations also confirmed the binding strength of SIQ17 in complex with EGFR. Overall, the potent SIQ compounds obtained in this work could be further optimized for developing novel anticancer drug candidates targeting EGFR-TK.