靶向降解细胞周期蛋白和细胞周期蛋白依赖性激酶作为癌症的治疗策略：综述

郑素雅; 陈烨; 诸志鹏; 李楠; 何春雨; H. Phillip KOEFFLER; 韩欣; 魏启春; 徐良

doi:10.1631/jzus.B2500021

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靶向降解细胞周期蛋白和细胞周期蛋白依赖性激酶作为癌症的治疗策略：综述

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Review | Updated：2025-08-25

靶向降解细胞周期蛋白和细胞周期蛋白依赖性激酶作为癌症的治疗策略：综述
Exploiting targeted degradation of cyclins and cyclin-dependent kinases for cancer therapeutics: a review
浙江大学学报（英文版）（B辑：生物医学和生物技术） 2025年26卷第8期页码：713-739
Affiliations：

1.Department of Surgical Oncology, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
2.Pediatric Cancer Research Center, National Clinical Research Center for Child Health, Hangzhou 310052, China
3.Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
4.Cancer Center, Zhejiang University, Hangzhou 310058, China
5.Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
6.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
7.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
8.Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou 310009, China
Funds：

the Zhejiang Provincial Natural Science Foundation of China(LZ23C060002;LZ24H160004);the National Natural Science Foundation of China(32270746;82203247;82203415;82272637;82204429;82073332);the National Key Research and Development Program of China(2022YFE0107800);the Medical Interdisciplinary Innovation Program 2024, Zhejiang University School of Medicine, and the Fundamental Research Funds for the Central Universities(K20220228);It is additionally supported by the National Institute of Health(R01-CA200992-03);philanthropic donations from the Leiomyosarcoma Support & Direct Research Foundation
DOI：10.1631/jzus.B2500021
中图分类号：
CSTR：
收稿日期：2025-01-12，

修回日期：2025-07-07，

纸质出版日期：2025-08-25
Accepted：

郑素雅,陈烨,诸志鹏等.靶向降解细胞周期蛋白和细胞周期蛋白依赖性激酶作为癌症的治疗策略：综述[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(08):713-739.

Suya ZHENG, Ye CHEN, Zhipeng ZHU, et al. Exploiting targeted degradation of cyclins and cyclin-dependent kinases for cancer therapeutics: a review[J]. Journal of zhejiang university-science b (biomedicine & biotechnology), 2025, 26(8): 713-739.
郑素雅,陈烨,诸志鹏等.靶向降解细胞周期蛋白和细胞周期蛋白依赖性激酶作为癌症的治疗策略：综述[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(08):713-739. DOI： 10.1631/jzus.B2500021.

Suya ZHENG, Ye CHEN, Zhipeng ZHU, et al. Exploiting targeted degradation of cyclins and cyclin-dependent kinases for cancer therapeutics: a review[J]. Journal of zhejiang university-science b (biomedicine & biotechnology), 2025, 26(8): 713-739. DOI： 10.1631/jzus.B2500021.

摘要

细胞异常增殖是癌症的主要特征。细胞周期蛋白（Cyclin）和细胞周期蛋白依赖性激酶（CDK）精密调控细胞周期，并参与DNA复制和转录、RNA剪接，以及蛋白质合成等关键过程。CDK信号通路失调在人类癌症的发生发展中广泛存在，这使得Cyclin与CDK蛋白成为极具潜力的治疗靶点。目前，多种CDK4/6抑制剂已展现出显著的抗癌疗效，并成功应用于临床，进一步推动了CDK靶向疗法的发展。伴随着CDK靶向抗癌药物研发的热潮，CDK靶向蛋白降解技术也取得了突破性进展，包括蛋白水解靶向嵌合体（proteolysis-targeting chimera）、HSP90介导的靶向嵌合体（HSP90-mediated targeting chimera）、疏水标签蛋白降解技术（hydrophobic tag）和分子胶（molecular glue）等。本综述聚焦Cyclin和CDK靶向策略及其临床转化，系统阐述了它们在癌症中的生物学功能，并总结了依赖蛋白酶体途径的Cyclin和CDK靶向降解的技术及作用原理。同时，本文系统梳理了现有的CDK降解剂的结构特征与活性，旨在通过分析其构效关系、靶标选择性与生物学效应，为CDK信号通路相关生物医学研究及癌症治疗提供重要参考。

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.

关键词

Keywords

references

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