Quinazoline-based fourth-generation EGFR tyrosine kinase inhibitors to overcome C797S-mediated resistance in non-small cell lung Cancer (NSCLC)

The emergence of resistance mutations, particularly C797S, in epidermal growth factor receptor tyrosine kinase (EGFR-TK) has significantly limited the long-term efficacy of Osimertinib in non-small cell lung cancer (NSCLC). In this study, we designed and evaluated a series of quinazoline derivatives targeting the triple mutant EGFR (L858R/T790M/C797S). Among them, compound 8d exhibited the highest potency against EGFR L858R/T790M/C797S, with an IC₅₀ of 0.068 μM, demonstrating strong binding affinity and effective suppression of kinase activity compared to Osimertinib. Molecular docking studies revealed key interactions with catalytic Lys745. Molecular dynamics (MD) simulations over 100 ns confirmed ligand stability, with an average root-mean-square deviation (RMSD) below 2.0 Å and a binding free energy of −44 kcal/mol (MM/GBSA). Structure-activity relationship (SAR) analysis highlighted the critical role of a bulkier hydrophobic substituent at the C2 position of the quinazoline ring in combination with a sulfonyl group, which improved affinity and potency. These findings establish quinazoline derivatives, particularly compound 8d, as promising fourth-generation EGFR inhibitors for overcoming C797S-mediated resistance in NSCLC therapy.