Current progress of 1,2,3-triazole hybrids as EGFR inhibitors for cancer therapy – a literature review

Abstract

Epidermal growth factor receptor (EGFR) is a validated oncogenic driver in numerous solid tumors, and resistance to first- and second-generation tyrosine kinase inhibitors continues to limit clinical outcomes. Epidermal growth factor receptor (EGFR) is a validated oncogenic driver in numerous solid tumors, and resistance to first- and second-generation tyrosine kinase inhibitors continues to limit clinical outcomes. In recent years, 1,2,3-triazole scaffolds have been extensively hybridized with diverse heterocycles to enhance potency, selectivity, and pharmacokinetic properties against wild-type and mutant EGFR. This review systematically classifies over 130 triazole-based EGFR inhibitors according to their co-scaffold architectures—including quinazoline, chromene/coumarin, pyridine/pyrimidine, quinoline, benzimidazole, indole, oxindole/isatin, imidazole, oxadiazole, thiadiazine, and natural-product-inspired hybrids—and analyzes structure–activity relationships (SAR), key hinge-binding interactions, docking and molecular dynamics insights, and ADMET profiles. For each class, we highlight lead compounds that achieved sub-nanomolar to low-micromolar EGFR inhibition, delineate substituent effects on kinase affinity and cellular antiproliferative activity, and discuss strategies to overcome common resistance mutations ( e.g. , L858R, T790M, C797S). Computational studies are integrated to reveal binding modes within the ATP-cleft and allosteric pockets, supporting the rational design of next-generation inhibitors. Finally, we identify current challenges—such as off-target toxicity and limited aqueous solubility—and propose future directions for optimizing triazole hybrids toward clinical translation. This scaffold-centric perspective aims to guide medicinal chemists in designing innovative triazole-based EGFR inhibitors with improved efficacy and safety profiles.