CDK4/6-related inhibitors from a medicinal chemistry perspective: Research advances in the past six years (2020-2025)

Cyclin-dependent kinase 4/6 (CDK4/6), as an important kinase regulating cell cycle progression, exhibits functional abnormalities closely associated with the initiation and progression of various cancers. Consequently, targeted inhibition of CDK4/6 represents a valuable and promising therapeutic strategy for cancer treatment. To date, multiple CDK4/6 inhibitors have been approved for market release and have demonstrated significant clinical efficacy. However, these drugs exhibit limited therapeutic versatility and carry substantial adverse effects. In recent years, significant progress has been made through systematic structural optimization of existing CDK4/6 inhibitors and the development of novel CDK4/6 inhibitors, such as dual-target inhibitors based on CDK4/6. This review aims to systematically summarize the research progress of CDK4/6 inhibitors over the past six years, focusing on their structural features, design strategies, and biological activity. Finally, we also discusses in detail the challenges and future directions for the discovery of CDK4/6-targeting drugs in cancer therapy.