Synthesis and evaluation of methoxyquinazoline sulfonamide derivatives as bifunctional molecular targeting tumor related inflammation and anti-EGFR triple-mutation

The development of novel anti-cancer compounds that overcome acquired resistance to third-generation EGFR inhibitors such as osimertinib is of great significance. This study designed and synthesized eighteen methoxyquinazoline sulfonamide derivatives, and evaluated their anti-tumor activity using three EGFR triple-mutant tumor cell lines. Among them, the optimal compound 9f exhibited IC₅₀ values of 33.3-95.3 nM against Baf3-L858R/C797S/T790M, Baf3-Del19/C797S/T790M, and H1975-L858R/C797S/T790M Cancer cell lines, which were consistent with the results of colony formation assays and 3D spheroid suspension culture assays. In anti-tumor experiments in mice bearing H1975-L858R/C797S/T790M tumors, compound 9f achieved a tumor growth inhibition rate of 67.3%. Mechanistic studies showed that 9f exerts excellent anti-inflammatory effects, including downregulating the expression of inflammation-related proteins iNOS, COX-2, and NF-κB (p65) in Raw264.7 cells (Western blot assay), increasing NO secretion in LPS-stimulated Raw264.7 cells (fluorescence intensity assay), and reducing IL-6 secretion in Raw264.7 and THP-1 cells (ELISA). Mechanistic studies also indicated that 9f promotes Apoptosis of tumor cells and inhibits phosphorylation of the key tumor growth protein EGFR.

Anti-inflammation; Co-culture; EGFR; Triple-mutation; Tumor microenvironment.