An EGFR-Targeting Oxothiazolidinylidene Derivative: From Computational Design to Experimental Validation

An oxothiazolidinylidene derivative, Ethyl (Z)-2-((Z)-3-(4-acetamidophenyl)-2-(((E)-1-(4-acetamidophenyl)ethylidene)hydrazono)-4-oxothiazolidin-5-ylidene)acetate ( Z-EAHT ) was rationally designed and evaluated as a potential epidermal growth factor receptor inhibitor targeting both wild-type and T790M mutant forms. Computational analyses demonstrated favorable electronic properties, strong ATP-binding pocket compatibility, and stable protein–ligand interactions supported by 200 ns molecular dynamics simulations and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) binding energy calculations. In silico ADME-Tox profiling predicted acceptable solubility, moderate absorption, and a favorable safety profile. Experimentally, Z-EAHT exhibited potent epidermal growth factor receptor inhibition (IC 50 = 0.012 µM for wild-type epidermal growth factor receptor; 0.013 µM for T790M mutant epidermal growth factor receptor) and demonstrated selective cytotoxicity against A549, MCF-7, and HepG-2 cancer cells while sparing normal WI-38 cells. Mechanistic investigations confirmed apoptosis induction and epidermal growth factor receptor downregulation. Overall, Z-EAHT emerged as a promising mutation-tolerant epidermal growth factor receptor inhibitor warranting further preclinical investigation.