CDK4/6-Based Drug Research and Development: A Four-Year Update.

INTRODUCTION CDK4/6 kinases are crucial cell cycle regulators, and pharmacological inhibition of these kinases to block the G1-to-S phase transition has become an integral part of modern cancer therapy. Although five CDK4/6 inhibitors have been clinically approved, the development of acquired drug resistance greatly limits their long-term therapeutic efficacy.

Methods

This review systematically summarizes the latest advances in CDK4/6 inhibitor research from 2022 to 2025, focusing on their structural features, biological functions, and preclinical research progress. In addition, this article comprehensively explores emerging therapeutic strategies, including bifunctional molecules and PROTAC-based protein degraders.

Results

The action mechanisms of conventional CDK4/6 inhibitors have been relatively well elucidated. Notably, these emerging strategies have yielded encouraging preclinical results, including co-targeting CDK4/6 with other critical therapeutic nodes (e.g., HDAC, PARP1) and adopting PROTAC-based degraders to directly induce the degradation of target proteins. A growing number of innovative approaches targeting drug resistance via multi-target inhibition and induced protein degradation have been developed. Distinct from classical singletarget monotherapy, these innovative strategies leverage distinct pharmacological pathways, offering feasible research directions to improve therapeutic efficacy and delay drug resistance.

Discussion

In-depth understanding of CDK4/6 inhibitors and the continuous development of bifunctional agents and protein degraders provides key theoretical and technical support for the design of next-generation therapeutic strategies to address current clinical limitations. These research advances are expected to facilitate the development of more effective and long-lasting therapeutic modalities for tumor treatment.

Conclusion

This review summarizes recent advances in CDK4/6 inhibitors. Novel dual-target and PROTACbased strategies offer promising resistance-overcoming tumor therapies.