Advancing EGFR-targeted anticancer strategies: the potential of thiazole, pyrazole, and thiazole–pyrazole hybrids

Background

As of 2025, the World Health Organization (WHO) reports that cancer remains a leading cause of death globally. The global Healthy Life Expectancy (HALE) at birth was estimated at 63.5 years in 2019, reflecting the average number of years a person can expect to live in full health. Chronic diseases like cancer significantly impact HALE, underscoring the need for effective interventions. The epidermal growth factor receptor (EGFR) is a validated therapeutic target, especially in cancers with EGFR overexpression or mutations. EGFR tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved clinical outcomes; however, resistance and limited efficacy in some patients demand the development of novel inhibitors. Heterocyclic scaffolds, such as thiazole and pyrazole, have garnered attention for their broad-spectrum anticancer properties, including EGFR inhibition. The synthesis of hybrid molecules combining thiazole and pyrazole cores has further enriched the scope of potential EGFR-targeted anticancer agents.

MainText

This review presents an in-depth analysis of thiazole, pyrazole, and their hybrid derivatives as promising EGFR-TKIs. We have summarized literature from 2008–2025, highlighting structure–activity relationship (SAR) trends, biochemical assay outcomes, and computational insights. The most potent compounds demonstrated submicromolar IC₅₀ values against EGFR and robust cytotoxicity in various cell lines. Conversely, least potent analogs often lacked these structural features or bore bulky or electron-donating groups at critical positions. Biochemical assays confirmed selective EGFR inhibition, while molecular docking and dynamics studies supported the favorable binding profiles of active compounds within the ATP-binding pocket of EGFR.

Conclusion

Thiazole, pyrazole, and their hybrids represent a promising class of EGFR-targeted anticancer agents. A combination of rational SAR-based modifications, supportive biochemical assay results, and computational modeling has laid the foundation for their further optimization. Continued efforts in hybrid design, guided by structural insights, may lead to the development of next-generation EGFR-TKIs capable of overcoming current therapeutic limitations.

Graphic abstract