Sulfonylated Indeno[1,2-c]quinoline Derivatives as Potent EGFR Tyrosine Kinase Inhibitors

The epidermal growth factor receptor (EGFR) has beenconsidereda potential target for lung cancer therapy due to its essential rolein regulating the survival and proliferation of cancer cells. Althougherlotinib, a potent EGFR tyrosine kinase (EGFR-TK) inhibitor, hasbeen used as the first-line drug for lung cancer treatment, acquireddrug resistance caused by the T790M secondary mutation of EGFR-TKinevitably develops after a median response duration of 9-13months. Thus, the search for promising compounds to effectively targetEGFR-TK has become an imperative necessity. In this study, the kinaseinhibitory activities of a series of sulfonylated indeno-[1,2-c]-quinolines (SIQs) against EGFR-TK were experimentallyand theoretically investigated. Among the 23 SIQ derivatives studied,eight compounds showed enhanced EGFR-TK inhibitory activity (IC50 values of ca. 0.6-10.2 nM) compared to the knowndrug erlotinib (IC50 of similar to 20 nM). In a cell-basedassay in human cancer cell lines with EGFR overexpression (A549 andA431 cells), the eight selected SIQs all showed more significant cytotoxicityagainst A431 than A549 cells, consistent with the higher EGFR expressionin A431 cells. Molecular docking and FMO-RIMP2/PCM calculations revealedthat SIQ17 occupies the ATP-binding site of EGFR-TK, where its sulfonylgroup is mainly stabilized by C797, L718, and E762 residues. Triplicate500 ns molecular dynamics (MD) simulations also confirmed the bindingstrength of SIQ17 in complex with EGFR. Overall, the potent SIQ compoundsobtained in this work could be further optimized for developing novelanticancer drug candidates targeting EGFR-TK.

Automated summary

This study investigated the kinase inhibitory activities of a series of sulfonylated indeno-[1,2-c]-quinolines (SIQs) against EGFR-TK. Among the 23 SIQ derivatives studied, eight compounds showed enhanced EGFR-TK inhibitory activity compared to erlotinib. In cell-based assays, these eight compounds exhibited more significant cytotoxicity against A431 cells with higher EGFR expression. Overall, the potent SIQ compounds obtained in this work could be further optimized for developing novel anticancer drug candidates targeting EGFR-TK.