Pyrimidine-based dual-target inhibitors targeting epidermal growth factor receptor for overcoming drug resistance in...

The epidermal growth factor receptor (EGFR) is a pivotal member of the epidermal growth factor receptor family, exerting crucial regulatory influence on cellular physiological processes, particularly in relation to cell growth, proliferation, and differentiation. In recent years, numerous EGFR inhibitors have been introduced to the market; unfortunately, the effectiveness of single-target EGFR inhibitors has been compromised due to the development of drug resistance caused by EGFR mutations. Despite attempts by some researchers to address this issue through combination therapy with two or more drugs, instances of dose-limiting toxicities have been observed. Consequently, EGFR dual-target inhibitors have emerged as a burgeoning field in cancer treatment, offering a novel therapeutic option for solid tumors with the added benefits of reduced risk of resistance, lower dosage requirements, diminished toxicity profiles, and enhanced efficacy. At present, a series of EGFR dual-target inhibitors with diverse structures have been developed successively. In this study, we initially investigated the pyrimidine-based EGFR dual-target inhibitors that have been reported in the past two decades and categorized them into aminopyrimidine derivatives and heterocyclic pyrimidine derivatives with increased molecular complexity. Subsequently, we comprehensively summarized the biological activity and structure-activity relationship of this class of inhibitors in the context of cancer therapy, while also exploring potential opportunities and challenges associated with their application in this field. The present study provides a partial framework to guide future endeavors in drug development.