Design and synthesis of novel EGFR kinase inhibitors for the treatment of EGFR C797S mutation in non-small cell lung cancer

Abstract Third-generation cutaneous growth factor receptor tyrosine kinase inhibitors have led to impressive advances in the treatment of non-small cell lung cancer. However, acquired resistance significantly limits the clinical application of these agents, with the epidermal growth factor receptor (EGFR)C797S mutation being the primary resistance mechanism. In this study, a series of novel EGFR kinase inhibitors was designed and synthesized for the treatment of the EGFRC797S mutation in non-small cell lung cancer. Structure activity relationship screening revealed that compound 5d was the most effective inhibitor of the C797S mutation. It strongly inhibited Baf3-EGFRL858R/T790M/C797S and Baf3-EGFR 19del/T790M/C797S cell lines, with IC50 values of 0.01836±0.0065 and 0.025±0.005 μM, respectively. Molecular docking studies showed that 5d binds to the EGFRL858R/T790M/C797S and EGFR19del/T790M/C797S proteins effectively. A mechanistic study showed that 5d induced cell cycle arrest in the G2/M phase. Compound 5d caused cell apoptosis in a dose-dependent manner, accompanied by a significant increase in the level of the apoptotic protein cleaved caspase-3. An in vivo xenograft assay of mice with Baf3-EGFR19del/T790M/C797S cells showed that 5d effectively inhibited tumor growth, with inhibition rates of 45.2% (70 mg/kg) and 55.7% (100 mg/kg) being observed. Therefore, 5d is worthy of further investigation as a fourth-generation EGFR inhibitor.