Optimizing Gefitinib for Toxicity Reduction and Dual-Route Administration: A Structure–Property–Toxicity Analysis

Gefitinib is a first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used to treat non-small cell lung cancer (NSCLC) with EGFR mutation.By binding competitively and reversibly to the ATP-binding pocket of the EGFR tyrosine kinase domain, gefitinib can block phosphorylation and downstream signal pathway.Due to its high membrane permeability but poor aqueous solubility, gefitinib is administered orally only.However, oral delivery requires the drug to go through the first-pass metabolism, which can form toxic reactive intermediates that contribute to hepatocellular injury by the oxidation process performed by liver enzymes like CYP2D6 and CYP3A4.Given these concerns, this study aimed to reduce hepatotoxicity, improve solubility, and explore the potential for dual-route administration (oral and intravenous) by designing five derivatives of gefitinib.Our findings showed that all derivatives successfully reduced hepatotoxicity from active to inactive status and had significant reductions in LogP values.We propose that derivative 2 is the best candidate in these five derivatives.It demonstrates a favorable LogP (2.91), strong EGFR binding affinity (-8.76 kcal/mol), more polar interactions, and reduced toxicities.However, derivative 3 achieves significant reductions in hepatotoxicity, specifically, and has the least number of active toxicity endpoints.It can only be considered as a capable future research target as it exhibits lower LD value, indicating higher acute toxicity, and has a LogP value of 1.08, which may be too soluble for oral drugs.These findings provide a computational basis for the development of gefitinib with improved pharmacological profiles.Still, we strongly recommend further experiments and clinical trials to validate the efficacy and safety of these five novel derivatives.