CDK4/6-Based Drug Research and Development: A Four-Year Update
Miao-Xia Pu1, Wen-Bo Xu1, Li Ding2
1Pharmaceutical Research Institute, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430205, China.
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.
Insights
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are vital cancer therapies, but drug resistance limits efficacy. Novel strategies like bifunctional molecules and PROTAC degraders show promise in overcoming resistance and improving long-term treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Cyclin-dependent kinase 4/6 (CDK4/6) kinases regulate cell cycle progression.
- CDK4/6 inhibitors are established cancer therapies blocking the G1-to-S phase transition.
- Acquired drug resistance to CDK4/6 inhibitors diminishes long-term therapeutic benefits.
Purpose of the Study:
- To review recent advances in CDK4/6 inhibitor research (2022-2025).
- To explore emerging therapeutic strategies for overcoming drug resistance.
- To provide insights for designing next-generation CDK4/6-targeted therapies.
Main Methods:
- Systematic review of preclinical and clinical research on CDK4/6 inhibitors.
- Focus on structural features, biological functions, and resistance mechanisms.
- Comprehensive exploration of novel strategies including bifunctional molecules and PROTACs.
Main Results:
- Established CDK4/6 inhibitors' mechanisms are well-understood.
- Emerging strategies like co-targeting (e.g., with HDAC, PARP1) show preclinical promise.
- PROTAC-based degraders effectively induce target protein degradation, offering new avenues against resistance.
Conclusions:
- Understanding CDK4/6 inhibitors and developing bifunctional agents/degraders supports next-generation therapy design.
- Innovative approaches like multi-target inhibition and induced protein degradation address resistance.
- These advances promise more effective and durable tumor treatments.
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