Pyrimidine derivatives as anticancer agents targeting kinases: design strategies, biological evaluation, and structure-activity relationship insights.

Protein kinases such as EGFR, VEGFR, PI3K, and CDKs play crucial roles in tumor progression and therapeutic resistance, making them prime targets in anticancer drug development. Among the structural scaffolds explored for designing selective kinase inhibitors, pyrimidine and its derivatives have emerged as highly privileged heterocycles due to their unique electronic properties, hydrogen-bonding capacity, and structural compatibility with kinase ATP-binding pockets. This review summarizes, recent advances in the design, synthesis, structure-activity relationship, and biological evaluation of pyrimidine-based inhibitors highlighting structural modification strategies such as molecular hybridization, bioisosterism, isosteric replacement and scaffold hopping approaches. The findings discussed in this review demonstrates that rational structural modification of the pyrimidine scaffold enables potent, selective, and multitarget kinase inhibition, positioning the versatility of pyrimidine derivatives as a privileged framework for the development of next-generation kinase-targeted anticancer agents with the potential to overcome therapeutic resistance.