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. 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.