Structure‐Activity Relationships of 2,4‐Disubstituted Pyrimidine Derivatives as EGFR Tyrosine Kinase Inhibitors in NSCLC: Impact of Substituent Hydrophobicity and Mutant Selectivity

ABSTRACT

Epidermal growth factor receptor (EGFR) mutations are major therapeutic targets in non‐small cell lung cancer (NSCLC), yet acquired resistance and wild‐type (WT) EGFR‐associated toxicity limit the durability of EGFR tyrosine kinase inhibitor (EGFR‐TKI) therapy. This review examines the structure activity relationships (SAR) of 2,4‐disubstituted pyrimidine‐based EGFR inhibitors reported from 2017 to 2026, focusing on 2‐ and 4‐position substitutions, mutant‐EGFR inhibition, T790M‐ and C797S‐associated resistance and physicochemical properties. Peer‐reviewed literature from PubMed, Scopus, Web of Science and ScienceDirect yielded 28 studies for qualitative analysis. Representative compounds were classified into four structural groups based on dominant 4‐position substituent features and compared using reported mutant and WT‐EGFR cellular activity, XlogP, molecular weight and topological polar surface area. Hydrophobic and fused heteroaromatic substituents often supported mutant‐EGFR activity when balanced with 2‐position substitution, polarity, steric complementarity, molecular orientation and protein‐ligand interactions. However, lipophilicity alone did not consistently predict potency or mutant selectivity. These findings support a context‐dependent structure‐physicochemical activity relationship rather than a universal hydrophobicity‐selectivity rule for designing next‐generation mutant‐selective EGFR inhibitors.