From single to dual targeting: Recent advances in EGFR-based dual inhibitors for cancer therapy.

Abstract

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase whose overexpression and activating mutations drive the pathogenesis of solid tumors, particularly non-small cell lung cancer (NSCLC). ATP-competitive EGFR inhibitors have progressed through four generations with considerable clinical success, yet their durability is limited by acquired mutations such as T790 M and C797S and by activation of compensatory signaling pathways. Dual-targeting inhibitors are single chemical entities designed to engage two distinct molecular targets simultaneously, generally constructed by conjugating, fusing or merging the pharmacophores of two established ligands. Conjugation offers synthetic flexibility but increases molecular size; fusion reduces molecular size at the cost of potential affinity loss; merging yields the most drug-like molecules but requires substantial pharmacophore overlap. EGFR-based dual inhibitors retain EGFR as the primary target and add a second oncogenic node such as HER2, VEGFR-2 or microtubules. The structural plasticity of the EGFR kinase domain, together with its well-characterized hinge, back-pocket and solvent-exposed regions, tolerates side-chain and linker modification and has made EGFR a favored scaffold for this approach. Clinically approved multi-targeting agents including vandetanib and neratinib provide proof of principle. Such molecules can simplify pharmacokinetics relative to drug combinations, although a single emergent mutation may abolish both activities and broader target coverage can reduce selectivity, so clinical superiority over combination regimens has to be demonstrated for each target pair. This review examines studies published between 2020 and 2026 on EGFR-based dual inhibitors spanning 26 secondary targets, addressing rational design, structure-activity relationships, receptor-ligand interaction profiles, and preclinical and clinical efficacy, and identifies the strategies most likely to resolve the current limitations of EGFR-centered multi-target therapy.