ABSTRACT Cancer remains a primary global health concern and is the second leading cause of mortality worldwide. Despite advances in chemotherapy and targeted therapies, issues such as multidrug resistance, limited selectivity, and severe adverse effects continue to impede effective treatment. Cyclin‐dependent kinase 2 (CDK2) has emerged as an attractive therapeutic target due to its key regulatory role in the G1/S transition of the cell cycle. In this regard, selective inhibition of CDK2 can arrest cell‐cycle progression, suppress proliferation, and induce apoptosis in cancer cells. In this review, comparative analysis of major heterocyclic scaffolds highlights clear differences in their ability to achieve ATP‐site recognition, hinge‐region engagement, and CDK2‐preferred binding modes. Furthermore, structure–activity relationship trends reveal that optimized hinge‐binding motifs, controlled hydrophobic pocket occupation and reduced steric congestion are key determinants of potency and CDK2 selectivity. This review critically summarizes recent advances in design of N ‐heterocyclic scaffolds as CDK2 inhibitors with focus on selectivity over closely related kinases such as CDK1, CDK4, and CDK6. However, many highly potent analogues suffer from suboptimal drug‐likeness and inconsistent in silico ADMET profiles that remain major translational challenges. Hence, emerging strategies are discussed as future directions to overcome resistance and pharmacokinetic limitations in CDK2‐targeted cancer therapy.
Chakraborty et al. (Wed,) studied this question.