Identification of sulfonylated indolo[1,2-a]quinolines as EGFR tyrosine kinase inhibitors†

Two series of indolo[1,2-a]quinolines (IQs), comprising six 6-trifluoromethylthio indolo[1,2-a]quinolines and nine 6-arenesulfonyl indolo[1,2-a]quinolines, were screened for their inhibitory activity against EGFR tyrosine kinase (EGFR-TK) using the ADP-Glo™ kinase assay. Among the 15 IQs screened, four compounds exhibited cytotoxic activity against a lung cancer cell line (A549) that was as potent as the known drug afatinib with lower cytotoxicity in Vero cells. In addition, while they displayed cytotoxic activity against a head and neck squamous cell carcinoma cell line (SCC cells), they were inactive against a colorectal cancer cell line (LS174T cells). Molecular dynamics (MD) simulations revealed that IQSO₂R-I (IC₅₀: 0.28 ± 0.05 μM) formed a stable complex with wild-type EGFR through hydrophohic interactions and hydrogen bonding with the K745 residue. Additionally, the compound complied with the extended rule of five. This class of compounds represents a novel class of EGFR-TK inhibitors, which may serve as a novel scaffold for the development of anticancer therapeutics targeting EGFR-TK.