Synthesis, Molecular Docking, and Biological Evaluation of Novel Chalcone Derivatives as Potent Dual Inhibitors of EGFR and HER2 in Lung Cancer Cell Lines

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, frequently driven by dysregulation of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). In this study, we report the design, synthesis, and biological evaluation of a novel series of chalcone derivatives (3a–l) as potent dual inhibitors of EGFR and HER2. The newly synthesized compounds were structurally characterized using 1H-NMR, 13C-NMR, and HRMS. In vitro cytotoxicity assays against A549 and H1975 lung cancer cell lines identified compound 3g, bearing a 4-dimethylamino group on the B-ring and a 4-chloro substitution on the A-ring, as the most potent lead, displaying IC50 values of 1.24 µM and 2.15 µM, respectively. Enzymatic assays confirmed that compound 3g effectively inhibited both EGFR (IC50 = 18.5 nM) and HER2 (IC50 = 34.2 nM). Molecular docking simulations revealed that 3g binds stably within the ATP-binding pockets of both kinases, forming key hydrogen bonds with Met793 (EGFR) and Met801 (HER2), along with strong hydrophobic interactions. Furthermore, compound 3g induced apoptosis in A549 cells and arrested the cell cycle at the G2/M phase. These findings highlight the potential of chalcone-based dual inhibitors as promising therapeutic candidates for the treatment of EGFR/HER2-driven lung cancers.