Design, Synthesis and Biological Effects Studies of Novel EGFR Inhibitors Targeting Wild-Type and Mutant EGFR...

Lung cancer remains one of the most significant global health challenges. Although EGFR inhibitors are actively employed in treatment, there is an urgent need for novel and effective inhibitors. In this context, a series of new EGFR inhibitors targeting both wild-type and mutant EGFR were designed and synthesized. The anticancer potentials of the synthesized derivatives were evaluated on A549 (lung cancer) and NIH/3T3 (healthy fibroblast) cell lines using the MTT method. Biological activity results revealed that the derivatives with 3,4-dichloro (2i) and 2,4-dichloro (2j) substitutions on the phenyl ring exhibited the highest potency in the series. Compound 2i showed superior efficacy against A549 cells with an IC₅₀ of 3.075 μM and a selective profile against healthy cells. Molecular docking studies (PDB: 4HJO, 2ITZ, 4I22) conducted to support the experimental data demonstrated that the active compounds were highly compatible with the ATP-binding pocket of EGFR. Structure-activity relationship (SAR) analyses showed that the specific halogen bonds formed by the dichloro derivatives with Met769/Met793 residues in the hinge region played a critical role in the activity enhancement. In enzyme inhibition tests, the success achieved by compound 2i at the nM level with an IC₅₀ = 0.096 μM against both the L858R and L858R-T790 M double mutant forms of EGFR confirmed the potential of this derivative to overcome clinical resistance mutations. In conclusion, the strong correlation between rational design, docking predictions, and biological activity results proves that the 3,4-dichloro (2i) modification is a key structural optimization in developing a next-generation EGFR inhibitor for the treatment of resistant lung cancer.