Exploiting targeted degradation of cyclins and cyclin-dependent kinases for cancer therapeutics: a review.

Suya ZHENG; Ye CHEN; Zhipeng ZHU; Nan LI; Chunyu HE; H Phillip KOEFFLER; Xin HAN; Qichun WEI; Liang XU

Return

Exploiting targeted degradation of cyclins and cyclin-dependent kinases for cancer therapeutics: a review.

Author: Suya ZHENG ¹ ; Ye CHEN ¹ ; Zhipeng ZHU ² ; Nan LI ¹ ; Chunyu HE ² ; H Phillip KOEFFLER ³ ; Xin HAN ⁴ ; Qichun WEI ⁵ ; Liang XU ⁶
Author Information

1. Department of Surgical Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China.
2. Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
3. Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
4. Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of The Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310009, China. xuliang.phd@zju.edu.cn, xinhan@zju.edu.cn.
5. Department of Radiation Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education and Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. xuliang.phd@zju.edu.cn, qichun_wei@zju.edu.cn.
6. Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou 310058, China. xuliang.phd@zju.edu.cn.
Publication Type:Review
Keywords: Cyclin; Cyclin-dependent kinase (CDK); Protein degrader; Targeted protein degradation
MeSH: Humans; Neoplasms/metabolism*; Cyclin-Dependent Kinases/antagonists & inhibitors*; Cyclins/metabolism*; Proteolysis; Antineoplastic Agents/pharmacology*; Molecular Targeted Therapy; Proteasome Endopeptidase Complex/metabolism*; Animals
From: Journal of Zhejiang University. Science. B 2025;26(8):713-739
CountryChina
Language:English
Abstract: Cancer is characterized by abnormal cell proliferation. Cyclins and cyclin-dependent kinases (CDKs) have been recognized as essential regulators of the intricate cell cycle, orchestrating DNA replication and transcription, RNA splicing, and protein synthesis. Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers, rendering cyclins and CDKs attractive therapeutic targets. Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use, fueling the development of CDK-targeted therapies. With this enthusiasm for finding novel CDK-targeting anti-cancer agents, there have also been exciting advances in the field of targeted protein degradation through innovative strategies, such as using proteolysis-targeting chimera, heat shock protein 90 (HSP90)‍-mediated targeting chimera, hydrophobic tag-based protein degradation, and molecular glue. With a focus on the translational potential of cyclin- and CDK-targeting strategies in cancer, this review presents the fundamental roles of cyclins and CDKs in cancer. Furthermore, it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs, detailing the underlying mechanisms of action for each approach. A comprehensive overview of the structure and activity of existing CDK degraders is also provided. By examining the structure‍‒‍activity relationships, target profiles, and biological effects of reported cyclin/CDK degraders, this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.