Role of Pyridine and Pyrimidine-Based Kinase Inhibitors in Cancer Treatment: Selectivity, Resistance, and Next-Generation Designs

Abstract

Pridine and pyrimidine scaffolds are important heterocyclic compounds; considerable attention is being paid to the development of anticancer drugs due to their utility as the foundational building blocks of DNA and RNA. Derivatives of pyridine are well established for their profound pharmacokinetic profiles, such as satisfactory solubility and metabolic stability, along with having demonstrably potent activity against important cancer targets like EGFR and VEGFR-2. Beyond their potential anticancer activity, a number of pyridine-based therapeutics offer diverse pharmacology, such as vasodilation and other relevant activities, broadening the scope of their therapeutic utility. The fused and standalone systems of pyrimidine derivatives have demonstrated impressive cytotoxic activity and interact with key molecular targets, primarily kinase enzymes, such as EGFR and VEGFR-2, which continue to be the focus of extensive investigation. This review, which includes the results from 2009 to 2025, synthesizes synthetic strategies. Compounds exhibiting kinase inhibition, DNA-binding affinity, and apoptosis induction are discussed, with emphasis on molecular docking insights and cytotoxic profiles across multiple cell lines. A comparative evaluation of their pharmacokinetic properties, scaffold advantages, and dual-inhibition strategies is also conducted. The review also outlines future directions for optimizing scaffolds, validating their mechanisms, and exploring their translational potential in oncology.