The evolving landscape of CDK2 inhibition in cancer: Therapeutic potential, clinical progress, and future directions.

Cyclin-dependent kinase 2 (CDK2) is a central orchestrator of G1/S and G2/M cell cycle progression. Its aberrant activation drives cancer progression in various malignancies, making CDK2 inhibition a promising therapeutic prospect. However, high structural similarity between CDK2 and family members like CDK1 and CDK5 has made discovering selective inhibitors with desirable safety and efficacy a two-decade-long challenge. CDK2 drives oncogenesis primarily in Cyclin E1 (CCNE1)-amplified and p16-high tumors. Furthermore, aberrant CDK2 signaling facilitates resistance against diverse chemotherapies and targeted agents, most significantly CDK4/6 inhibitors. While dispensable for most normal cells, CDK2 can be activated as a mediator of renal and cardiovascular toxicity during chemotherapy. Emerging evidence also identifies a novel immunomodulatory role for CDK2, where its inhibition may potentiate immune checkpoint blockade. Recently, multiple selective CDK2 inhibitors have entered clinical trials, showing promising early signals of efficacy and safety. This review provides a comprehensive and up-to-date synthesis of the multifaceted roles of CDK2 in cancer, examining the landscape of selective CDK2 inhibitors and next-generation degraders (PROTACs/Molecular Glues) currently in clinical pipelines. We critically analyze translational hurdles-including the quest for super-selectivity over CDK1, the validation of predictive biomarkers, and resistance mapping-to provide a strategic direction for the future of CDK2-based cancer therapeutics.