Targeting cyclin-dependent kinases in cancer: emerging therapeutics and clinical strategies

Cyclin-dependent kinases (CDKs) regulate cell cycle progression, and their dysregulation is a hallmark of cancer. CDK4/6 inhibitors have shown clinical success against hormone receptor (HR)-positive, Human epidermal growth factor receptor (HER2)-negative breast cancer but encounter adaptive resistance, dose-limiting toxicities, and limited activity in other tumor contexts. Emerging strategies include CDK4-selective, CDK2-selective, and pan-CDK2/4/6 inhibitors designed to overcome resistance and enhance tolerability. In parallel, novel modalities such as proteolysis-targeting degraders, molecular glue degraders, and cyclin-directed agents offer new opportunities to exploit cell cycle vulnerabilities. Several of these candidates have entered early-phase clinical evaluation, marking a new era in CDK-targeted therapy. This review synthesizes recent preclinical and clinical advances, defines key challenges in optimizing efficacy and safety, and outlines future directions for integrating CDK-directed strategies within precision oncology frameworks.