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

doi:10.1631/jzus.B2500021

Your Location：

Home >

Browse articles >

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

Scan QR Code

Alert me when the article has been cited

Submit

Review | Updated：2025-08-25

Exploiting targeted degradation of cyclins and cyclin-dependent kinases for cancer therapeutics: a review
Exploiting targeted degradation of cyclins and cyclin-dependent kinases for cancer therapeutics: a review
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
Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) Vol. 26, Issue 8, Pages: 713-739(2025)
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：
DOI：10.1631/jzus.B2500021
CLC：
CSTR：
Received：12 January 2025，

Revised：07 July 2025，

Published：25 August 2025
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

Adhikari B , Bozilovic J , Diebold M , et al. , 2020 . PROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase . Nat Chem Biol , 16 ( 11 ): 1179 - 1188 . https://doi.org/10.1038/s41589-020-00652-y https://doi.org/10.1038/s41589-020-00652-y

Anderson NA , Cryan J , Ahmed A , et al. , 2020 . Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs . Bioorg Med Chem Lett , 30 ( 9 ): 127106 . https://doi.org/10.1016/j.bmcl.2020.127106 https://doi.org/10.1016/j.bmcl.2020.127106

Ao MT , Wu J , Cao Y , et al. , 2023 . The synthesis of PROTAC molecule and new target KAT6A identification of CDK9 inhibitor iCDK9 . Chin Chem Lett , 34 ( 4 ): 107741 . https://doi.org/10.1016/j.cclet.2022.107741 https://doi.org/10.1016/j.cclet.2022.107741

Asghar U , Witkiewicz AK , Turner NC , et al. , 2015 . The history and future of targeting cyclin-dependent kinases in cancer therapy . Nat Revi Drug Discov , 14 ( 2 ): 130 - 146 . https://doi.org/10.1038/nrd4504 https://doi.org/10.1038/nrd4504

Aublette MC , Harrison TA , Thorpe EJ , et al. , 2022 . Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases . Bioorg Med Chem Lett , 64 : 128636 . https://doi.org/10.1016/j.bmcl.2022.128636 https://doi.org/10.1016/j.bmcl.2022.128636

Bai X , Guo ZQ , Zhang YP , et al. , 2023 . CDK4/6 inhibition triggers ICAM1-driven immune response and sensitizes LKB1 mutant lung cancer to immunotherapy . Nat Commun , 14 : 1247 . https://doi.org/10.1038/s41467-023-36892-4 https://doi.org/10.1038/s41467-023-36892-4

Baumli S , Lolli G , Lowe ED , et al. , 2008 . The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation . EMBO J , 27 ( 13 ): 1907 - 1918 . https://doi.org/10.1038/emboj.2008.121 https://doi.org/10.1038/emboj.2008.121

Békés M , Langley DR , Crews CM , 2022 . PROTAC targeted protein degraders: the past is prologue . Nate Rev Drug Discov , 21 ( 3 ): 181 - 200 . https://doi.org/10.1038/s41573-021-00371-6 https://doi.org/10.1038/s41573-021-00371-6

Bösken CA , Farnung L , Hintermair C , et al. , 2014 . The structure and substrate specificity of human Cdk12/Cyclin K . Nat Commun , 5 : 3505 . https://doi.org/10.1038/ncomms4505 https://doi.org/10.1038/ncomms4505

Boyer LA , Lee TI , Cole MF , et al. , 2005 . Core transcriptional regulatory circuitry in human embryonic stem cells . Cell , 122 ( 6 ): 947 - 956 . https://doi.org/10.1016/j.cell.2005.08.020 https://doi.org/10.1016/j.cell.2005.08.020

Brand M , Jiang BS , Bauer S , et al. , 2019 . Homolog-selective degradation as a strategy to probe the function of CDK6 in AML . Cell Chem Biol , 26 ( 2 ): 300 - 306.e9 . https://doi.org/10.1016/j.chembiol.2018.11.006 https://doi.org/10.1016/j.chembiol.2018.11.006

Cancer Genome Atlas Research Network , 2011 . Integrated genomic analyses of ovarian carcinoma . Nature , 474 ( 7353 ): 609 - 615 . https://doi.org/10.1038/nature10166 https://doi.org/10.1038/nature10166

Chen MQ , Li J , Zhang L , et al. , 2023 . CDK8 and CDK19: positive regulators of signal-induced transcription and negative regulators of Mediator complex proteins . Nucleic Acids Res , 51 ( 14 ): 7288 - 7313 . https://doi.org/10.1093/nar/gkad538 https://doi.org/10.1093/nar/gkad538

Cheng L , Zhou SC , Zhou SQ , et al. , 2022 . Dual inhibition of CDK12/CDK13 targets both tumor and immune cells in ovarian cancer . Cancer Res , 82 ( 19 ): 3588 - 3602 . https://doi.org/10.1158/0008-5472.CAN-22-0222 https://doi.org/10.1158/0008-5472.CAN-22-0222

Chi J , Li HC , Zhou Z , et al. , 2019 . A novel strategy to block mitotic progression for targeted therapy . eBioMedicine , 49 : 40 - 54 . https://doi.org/10.1016/j.ebiom.2019.10.013 https://doi.org/10.1016/j.ebiom.2019.10.013

Chipumuro E , Marco E , Christensen CL , et al. , 2014 . CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer . Cell , 159 ( 5 ):‍‍ 1126 - 1139 . https://doi.org/10.1016/j.cell.2014.10.024 https://doi.org/10.1016/j.cell.2014.10.024

Chirnomas D , Hornberger KR , Crews CM , 2023 . Protein degraders enter the clinic‍—a new approach to cancer therapy . Nat Rev Clin Oncol , 20 ( 4 ): 265 - 278 . https://doi.org/10.1038/s41571-023-00736-3 https://doi.org/10.1038/s41571-023-00736-3

Choi SH , Kim S , Jones KA , 2020 . Gene expression regulation by CDK12: a versatile kinase in cancer with functions beyond CTD phosphorylation . Exp Mol Med , 52 ( 5 ): 762 - 771 . https://doi.org/10.1038/s12276-020-0442-9 https://doi.org/10.1038/s12276-020-0442-9

Chou CL , Lin CT , Kao CT , et al. , 2024 . A novel rational PROTACs design and validation via AI-driven drug design approach . ACS Omega , 9 ( 37 ): 38371 - 38384 . https://doi.org/10.1021/acsomega.3c10183 https://doi.org/10.1021/acsomega.3c10183

Chou J , Quigley DA , Robinson TM , et al. , 2020 . Transcription-associated cyclin-dependent kinases as targets and biomarkers for cancer therapy . Cancer Discov , 10 ( 3 ): 351 - 370 . https://doi.org/10.1158/2159-8290.CD-19-0528 https://doi.org/10.1158/2159-8290.CD-19-0528

Christensen CL , Kwiatkowski N , Abraham BJ , et al. , 2014 . Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor . Cancer Cell , 26 ( 6 ): 909 - 922 . https://doi.org/10.1016/j.ccell.2014.10.019 https://doi.org/10.1016/j.ccell.2014.10.019

Condorelli R , Spring L , O’Shaughnessy J , et al. , 2018 . Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer . Ann Oncol , 29 ( 3 ): 640 - 645 . https://doi.org/10.1093/annonc/mdx784 https://doi.org/10.1093/annonc/mdx784

Cornwell JA , Crncec A , Afifi MM , et al. , 2023 . Loss of CDK4/6 activity in S/G2 phase leads to cell cycle reversal . Nature , 619 ( 7969 ): 363 - 370 . https://doi.org/10.1038/s41586-023-06274-3 https://doi.org/10.1038/s41586-023-06274-3

de Dominici M , Porazzi P , Xiao YC , et al. , 2020 . Selective inhibition of Ph-positive ALL cell growth through kinase-dependent and -independent effects by CDK6-specific PROTACs . Blood , 135 ( 18 ): 1560 - 1573 . https://doi.org/10.1182/blood.2019003604 https://doi.org/10.1182/blood.2019003604

Deshaies RJ , 2015 . Prime time for PROTACs . Nat Chem Biol , 11 ( 9 ): 634 - 635 . https://doi.org/10.1038/nchembio.1887 https://doi.org/10.1038/nchembio.1887

Dieci G , 2021 . Removing quote marks from the RNA polymerase II CTD ‘code’ . Biosystems , 207 : 104468 . https://doi.org/10.1016/j.biosystems.2021.104468 https://doi.org/10.1016/j.biosystems.2021.104468

Dieter SM , Siegl C , Codó PL , et al. , 2021 . Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer . Cell Rep , 36 ( 3 ): 109394 . https://doi.org/10.1016/j.celrep.2021.109394 https://doi.org/10.1016/j.celrep.2021.109394

Dogan S , Shen RL , Ang DC , et al. , 2012 . Molecular epidemiology of EGFR and KRAS mutations in 3026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS -mutant cancers . Clin Cancer Res , 18 ( 22 ): 6169 - 6177 . https://doi.org/10.1158/1078-0432.CCR-11-3265 https://doi.org/10.1158/1078-0432.CCR-11-3265

Donovan KA , Ferguson FM , Bushman JW , et al. , 2020 . Mapping the degradable kinome provides a resource for exped ited degrader development. Cell , 183 ( 6 ):‍ 1714 - 1731.e10 . https://doi.org/10.1016/j.cell.2020.10.038 https://doi.org/10.1016/j.cell.2020.10.038

Dubbury SJ , Boutz PL , Sharp PA , 2018 . CDK12 regulates DNA repair genes by suppressing intronic polyadenylation . Nature , 564 ( 7734 ): 141 - 145 . https://doi.org/10.1038/s41586-018-0758-y https://doi.org/10.1038/s41586-018-0758-y

Fan HM , Liu WC , Zeng YQ , et al. , 2023 . DNA damage induced by CDK4 and CDK6 blockade triggers anti-tumor immune responses through cGAS-STING pathway . Commun Biol , 6 : 1041 . https://doi.org/10.1038/s42003-023-05412-x https://doi.org/10.1038/s42003-023-05412-x

Fan Z , Devlin JR , Hogg SJ , et al. , 2020 . CDK13 cooperates with CDK12 to control global RNA polymerase II processivity . Sci Adv , 6 ( 18 ): eaaz5041 . https://doi.org/10.1126/sciadv.aaz5041 https://doi.org/10.1126/sciadv.aaz5041

Filippakopoulos P , Picaud S , Mangos M , et al. , 2012 . Histone recognition and large-scale structural analysis of the human bromodomain family . Cell , 149 ( 1 ): 214 - 231 . https://doi.org/10.1016/j.cell.2012.02.013 https://doi.org/10.1016/j.cell.2012.02.013

Gan XL , Wang F , Luo JG , et al. , 2024 . Proteolysis Targeting Chimeras (PROTACs) based on celastrol induce multiple protein degradation for triple-negative breast cancer treatment . Eur J Pharm Sci , 192 : 106624 . https://doi.org/10.1016/j.ejps.2023.106624 https://doi.org/10.1016/j.ejps.2023.106624

Glover-Cutter K , Larochelle S , Erickson B , et al. , 2009 . TFIIH-associated Cdk7 kinase functions in phosphorylation of C-terminal domain Ser7 residues, promoter-proximal pausing, and termination by RNA polymerase II . Mol Cell Biol , 29 ( 20 ): 5455 - 5464 . https://doi.org/10.1128/MCB.00637-09 https://doi.org/10.1128/MCB.00637-09

Goel S , DeCristo MJ , Watt AC , et al. , 2017 . CDK4/6 inhibition triggers anti-tumour immunity . Nature , 548 ( 7668 ): 471 - 475 . https://doi.org/10.1038/nature23465 https://doi.org/10.1038/nature23465

Goel S , Bergholz JS , Zhao JJ , 2022 . Targeting CDK4 and CDK6 in cancer . Nat Rev Cancer , 22 ( 6 ): 356 - 372 . https://doi.org/10.1038/s41568-022-00456-3 https://doi.org/10.1038/s41568-022-00456-3

Gordon V , Bhadel S , Wunderlich W , et al. , 2010 . CDK9 regulates AR promoter selectivity and cell growth through serine 81 phosphorylation . Mol Endocrinol , 24 ( 12 ):‍ 2267 - 2280 . https://doi.org/10.1210/me.2010-0238 https://doi.org/10.1210/me.2010-0238

Hatcher JM , Wang ES , Johannessen L , et al. , 2018 . Development of highly potent and selective steroidal inhibitors and degraders of CDK8 . ACS Med Chem Lett , 9 ( 6 ):‍ 540 - 545 . https://doi.org/10.1021/acsmedchemlett.8b00011 https://doi.org/10.1021/acsmedchemlett.8b00011

Hati S , Zallocchi M , Hazlitt R , et al. , 2021 . AZD5438-PROTAC: a selective CDK2 degrader that protects against cisplatin- and noise-induced hearing loss . Eur J Med Chem , 226 : 113849 . https://doi.org/10.1016/j.ejmech.2021.113849 https://doi.org/10.1016/j.ejmech.2021.113849

He H , Zhang XS , Wang J , et al. , 2024 . Development of degraders of cyclin-dependent kinases 4 and 6 based on rational drug design . J Med Chem , 67 ( 13 ): 11354 - 11364 . https://doi.org/10.1021/acs.jmedchem.4c00965 https://doi.org/10.1021/acs.jmedchem.4c00965

Houles T , Boucher J , Lavoie G , et al. , 2023 . The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma . Cell Death Discov , 9 : 459 . https://doi.org/10.1038/s41420-023-01754-x https://doi.org/10.1038/s41420-023-01754-x

Hu AJ , Li W , Pathak A , et al. , 2023 . CDK6 is essential for mesenchymal stem cell proliferation and adipocyte differentiation . Front Mol Biosci , 10 : 1146047 . https://doi.org/10.3389/fmolb.2023.1146047 https://doi.org/10.3389/fmolb.2023.1146047

Hu C , Shen LJ , Zou FM , et al. , 2023 . Predicting and overcoming resistance to CDK9 inhibitors for cancer therapy . Acta Pharm Sin B , 13 ( 9 ): 3694 - 3707 . https://doi.org/10.1016/j.apsb.2023.05.026 https://doi.org/10.1016/j.apsb.2023.05.026

Huang HT , Dobrovolsky D , Paulk J , et al. , 2018 . A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader . Cell Chem Biol , 25 ( 1 ): 88 - 99.e6 . https://doi.org/10.1016/j.chembiol.2017.10.005 https://doi.org/10.1016/j.chembiol.2017.10.005

Huang XD , Dixit VM , 2016 . Drugging the undruggables: exploring the ubiquitin system for drug development . Cell Res , 26 ( 4 ): 484 - 498 . https://doi.org/10.1038/cr.2016.31 https://doi.org/10.1038/cr.2016.31

Huang YG , Liu WW , Zhao CH , et al. , 2024 . Targeting cyclin-dependent kinases: from pocket specificity to drug selectivity . Eur J Med Chem , 275 : 116547 . https://doi.org/10.1016/j.ejmech.2024.116547 https://doi.org/10.1016/j.ejmech.2024.116547

Hydbring P , Malumbres M , Sicinski P , 2016 . Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases . Nat Rev Mol Cell Biol , 17 ( 5 ): 280 - 292 . https://doi.org/10.1038/nrm.2016.27 https://doi.org/10.1038/nrm.2016.27

Iniguez AB , Stolte B , Wang EJ , et al. , 2018 . EWS/FLI confers tumor cell synthetic lethality to CDK12 inhibition in Ewing sarcoma . Cancer Cell , 33 ( 2 ): 202 - 216.e6 . https://doi.org/10.1016/j.ccell.2017.12.009 https://doi.org/10.1016/j.ccell.2017.12.009

Ishida T , Ciulli A , 2021 . E3 ligase ligands for PROTACs: how they were found and how to discover new ones . SLAS Discov , 26 ( 4 ): 484 - 502 . https://doi.org/10.1177/2472555220965528 https://doi.org/10.1177/2472555220965528

Ji WZ , Du GY , Jiang J , et al. , 2024 . Discovery of bivalent small molecule degraders of cyclin-dependent kinase 7 (CDK7) . Eur J Med Chem , 276 : 116613 . https://doi.org/10.1016/j.ejmech.2024.116613 https://doi.org/10.1016/j.ejmech.2024.116613

Jiang BS , Wang ES , Donovan KA , et al. , 2019 . Development of dual and selective degraders of cyclin-dependent kinases 4 and 6 . Angew Chem Int Ed , 58 ( 19 ): 6321 - 6326 . https://doi.org/10.1002/anie.201901336 https://doi.org/10.1002/anie.201901336

Kargbo RB , 2021 . Tumor-targeted bivalent protein degradation for application in cancer therapy . ACS Med Chem Lett , 12 ( 3 ): 326 - 327 . https://doi.org/10.1021/acsmedchemlett.1c00084 https://doi.org/10.1021/acsmedchemlett.1c00084

Kciuk M , Gielecińska A , Mujwar S , et al. , 2022 . Cyclin-dependent kinases in DNA damage response . Biochim Biophys Acta Rev Cancer , 1877 ( 3 ): 188716 . https://doi.org/10.1016/j.bbcan.2022.188716 https://doi.org/10.1016/j.bbcan.2022.188716

King HM , Rana S , Kubica SP , et al. , 2021 . Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax . Bioorg Med Chem Lett , 43 : 128061 . https://doi.org/10.1016/j.bmcl.2021.128061 https://doi.org/10.1016/j.bmcl.2021.128061

Kozicka Z , Suchyta DJ , Focht V , et al. , 2024 . Design principles for cyclin K molecular glue degraders . Nat Chem Biol , 20 ( 1 ): 93 - 102 . https://doi.org/10.1038/s41589-023-01409-z https://doi.org/10.1038/s41589-023-01409-z

Krajewska M , Dries R , Grassetti AV , et al. , 2019 . CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation . Nat Commun , 10 : 1757 . https://doi.org/10.1038/s41467-019-09703-y https://doi.org/10.1038/s41467-019-09703-y

Kumarasamy V , Gao Z , Zhao BS , et al. , 2023 . PROTAC-mediated CDK degradation differentially impacts cancer cell cycles due to heterogeneity in kinase dependencies . Br J Cancer , 129 ( 8 ): 1238 - 1250 . https://doi.org/10.1038/s41416-023-02399-4 https://doi.org/10.1038/s41416-023-02399-4

Leiser D , Pochon B , Blank-Liss W , et al. , 2014 . Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation . FEBS Lett , 588 ( 5 ): 653 - 658 . https://doi.org/10.1016/j.febslet.2013.12.025 https://doi.org/10.1016/j.febslet.2013.12.025

Li FL , Hu QY , Zhang XL , et al. , 2022 . DeepPROTACs is a deep learning-based targeted degradation predictor for PROTACs . Nat Commun , 13 : 7133 . https://doi.org/10.1038/s41467-022-34807-3 https://doi.org/10.1038/s41467-022-34807-3

Li JC , Liu T , Song YL , et al. , 2022 . Discovery of small-molecule degraders of the CDK9-cyclin T1 complex for targeting transcriptional addiction in prostate cancer . J Med Chem , 65 ( 16 ): 11034 - 11057 . https://doi.org/10.1021/acs.jmedchem.2c00257 https://doi.org/10.1021/acs.jmedchem.2c00257

Li Q , Jiang BS , Guo JY , et al. , 2022 . INK4 tumor suppressor proteins mediate resistance to CDK4/6 kinase inhibitors . Cancer Discov , 12 ( 2 ): 356 - 371 . https://doi.org/10.1158/2159-8290.CD-20-1726 https://doi.org/10.1158/2159-8290.CD-20-1726

Li Z , Wang FC , Tian XX , et al. , 2021 . HCK maintains the self-renewal of leukaemia stem cells via CDK6 in AML . J Exp Clin Cancer Res , 40 : 210 . https://doi.org/10.1186/s13046-021-02007-4 https://doi.org/10.1186/s13046-021-02007-4

Li ZZ , Ma SY , Zhang L , et al. , 2023 . Targeted protein degradation induced by HEMTACs based on HSP90 . J Med Chem , 66 ( 1 ): 733 - 751 . https://doi.org/10.1021/acs.jmedchem.2c01648 https://doi.org/10.1021/acs.jmedchem.2c01648

Lin RK , Yang J , Liu T , et al. , 2023 . Discovery of HyT-based degraders of CDK9-cyclin T1 complex . Chem Biodivers , 20 ( 8 ): e202300769 . https://doi.org/10.1002/cbdv.202300769 https://doi.org/10.1002/cbdv.202300769

Liu F , Wang X , Duan JL , et al. , 2022 . A temporal PROTAC cocktail-mediated sequential degradation of AURKA abrogates acute myeloid leukemia stem cells . Adv Sci , 9 ( 22 ): e2104823 . https://doi.org/10.1002/advs.202104823 https://doi.org/10.1002/advs.202104823

Liu Y , Yang JW , Wang TL , et al. , 2023 . Expanding PROTACtable genome universe of E3 ligases . Nat Commun , 1 : 6509 . https://doi.org/10.1038/s41467-023-42233-2 https://doi.org/10.1038/s41467-023-42233-2

Lu G , Middleton RE , Sun HH , et al. , 2014 . The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins . Science , 343 ( 6168 ): 305 - 309 . https://doi.org/10.1126/science.1244917 https://doi.org/10.1126/science.1244917

Luo YL , Song DY , Zhang CW , et al. , 2025 . ProLinker‍–generator: design of a PROTAC linker base on a generation model using transfer and reinforcement learning . Appl Sci , 15 ( 10 ): 5616 . https://doi.org/10.3390/app15105616 https://doi.org/10.3390/app15105616

Lv L , Chen PH , Cao LZ , et al. , 2020 . Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation . eLife , 9 : e59994 . https://doi.org/10.7554/eLife.59994 https://doi.org/10.7554/eLife.59994

Magnuson B , Bedi K , Narayanan IV , et al. , 2022 . CDK12 re

gulates co-transcriptional splicing and RNA turnover in human cells . iScience , 25 ( 9 ): 105030 . https://doi.org/10.1016/j.isci.2022.105030 https://doi.org/10.1016/j.isci.2022.105030

Marineau JJ , Hamman KB , Hu SH , et al. , 2022 . Discovery of SY-5609: a selective, noncovalent inhibitor of CDK7 . J Med Chem , 65 ( 2 ): 1458 - 1480 . https://doi.org/10.1021/acs.jmedchem.1c01171 https://doi.org/10.1021/acs.jmedchem.1c01171

Maurer B , Brandstoetter T , Kollmann S , et al. , 2021 . Inducible deletion of CDK4 and CDK6 – deciphering CDK4/6 inhibitor effects in the hematopoietic system . Haematologica , 106 ( 10 ): 2624 - 2632 . https://doi.org/10.3324/haematol.2020.256313 https://doi.org/10.3324/haematol.2020.256313

Mayor-Ruiz C , Bauer S , Brand M , et al. , 2020 . Rational discovery of molecular glue degraders via scalable chemical profiling . Nat Chem Biol , 16 ( 11 ): 1199 - 1207 . https://doi.org/10.1038/s41589-020-0594-x https://doi.org/10.1038/s41589-020-0594-x

Mbonye UR , Gokulrangan G , Datt M , et al. , 2013 . Phosphorylation of CDK9 at Ser175 enhances HIV transcription and is a marker of activated P-TEFb in CD4 + T lymph ocytes . PLoS Pathogens , 9 ( 5 ): e1003338 . https://doi.org/10.1371/journal.ppat.1003338 https://doi.org/10.1371/journal.ppat.1003338

McKenney C , Lendner Y , Guerrero Zuniga A , et al. , 2024 . CDK4/6 activity is required during G 2 arrest to prevent stress-induced endoreplication . Science , 384 ( 6695 ): eadi2421 . https://doi.org/10.1126/science.adi2421 https://doi.org/10.1126/science.adi2421

Menzl I , Zhang TH , Berger-Becvar A , et al. , 2019 . A kinase-independent role for CDK8 in BCR-ABL1 + leukemia . Nat Commun , 10 : 4741 . https://doi.org/10.1038/s41467-019-12656-x https://doi.org/10.1038/s41467-019-12656-x

Moon S , Lee BH , 2018 . Chemically induced cellular proteolysis: an emerging therapeutic strategy for undruggable targets . Mol Cells , 41 ( 11 ): 933 - 942 . https://doi.org/10.14348/molcells.2018.0372 https://doi.org/10.14348/molcells.2018.0372

Morrison L , Loibl S , Turner NC , 2024 . The CDK4/6 inhibitor revolution – a game-changing era for breast cancer treatment . Nat Rev Clin Oncol , 21 ( 2 ): 89 - 105 . https://doi.org/10.1038/s41571-023-00840-4 https://doi.org/10.1038/s41571-023-00840-4

Nayyar N , de Sauvage MA , Chuprin J , et al. , 2024 . CDK4/6 inhibition sensitizes intracranial tumors to PD-1 blockade in preclinical models of brain metastasis . Clin Cancer Res , 30 ( 2 ): 420 - 435 . https://doi.org/10.1158/1078-0432.CCR-23-0433 https://doi.org/10.1158/1078-0432.CCR-23-0433

Neklesa TK , Tae HS , Schneekloth AR , et al. , 2011 . Small-molecule hydrophobic tagging-induced degradation of HaloTag fusion proteins . Nat Chem Biol , 7 ( 8 ): 538 - 543 . https://doi.org/10.1038/nchembio.597 https://doi.org/10.1038/nchembio.597

Niu T , Li KL , Jiang L , et al. , 2022 . Noncovalent CDK12/13 dual inhibitors-based PROTACs degrade CDK12-Cyclin K complex and induce synthetic lethality with PARP inhibitor . Eur J Med Chem , 228 : 114012 . https://doi.org/10.1016/j.ejmech.2021.114012 https://doi.org/10.1016/j.ejmech.2021.114012

Olson CM , Jiang BS , Erb MA , et al. , 2018 . Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation . Nat Chem Biol , 14 ( 2 ): 163 - 170 . https://doi.org/10.1038/nchembio.2538 https://doi.org/10.1038/nchembio.2538

Palmer CL , Boras B , Pascual B , et al. , 2025 . CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety . Cancer Cell , 43 ( 3 ): 464 - 481.e14 . https://doi.org/10.1016/j.ccell.2025.02.006 https://doi.org/10.1016/j.ccell.2025.02.006

Parua PK , Fisher RP , 2020 . Dissecting the Pol II transcription cycle and derailing cancer with CDK inhibitors . Nat Chem Biol , 16 ( 7 ): 716 - 724 . https://doi.org/10.1038/s41589-020-0563-4 https://doi.org/10.1038/s41589-020-0563-4

Petroni G , Formenti SC , Chen-Kiang S , et al. , 2020 . Immunomodulation by anticancer cell cycle inhibitors . Nat Rev Immunol , 20 ( 11 ): 669 - 679 . https://doi.org/10.1038/s41577-020-0300-y https://doi.org/10.1038/s41577-020-0300-y

Pluta AJ , Studniarek C , Murphy S , et al. , 2024 . Cyclin-dependent kinases: masters of the eukaryotic universe . WIREs RNA , 15 ( 1 ): e1816 . https://doi.org/10.1002/wrna.1816 https://doi.org/10.1002/wrna.1816

Pu CL , Liu YY , Deng R , et al. , 2023 . Development of PROTAC degrader probe of CDK4/6 based on DCAF16 . Bioorg Chem , 138 : 106637 . https://doi.org/10.1016/j.bioorg.2023.106637 https://doi.org/10.1016/j.bioorg.2023.106637

Qiu M , Yin ZN , Wang HH , et al. , 2023 . CDK12 and Integrator-PP2A complex modulates LEO1 phosphorylation for processive transcription elongation . Sci Adv , 9 ( 20 ): eadf8698 . https://doi.org/10.1126/sciadv.adf8698 https://doi.org/10.1126/sciadv.adf8698

Qiu XQ , Li YQ , Yu B , et al. , 2021 . Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion . Eur J Med Chem , 211 : 113091 . https://doi.org/10.1016/j.ejmech.2020.113091 https://doi.org/10.1016/j.ejmech.2020.113091

Quandt E , Ribeiro MPC , Clotet J , 2020 . Atypical cyclins: the extended family portrait . Cell Mol Life Sci , 77 ( 2 ): 231 - 242 . https://doi.org/10.1007/s00018-019-03262-7 https://doi.org/10.1007/s00018-019-03262-7

Quandt E , Masip N , Hernández-Ortega S , et al. , 2023 . CDK6 is activated by the atypical cyclin I to promote E2F-mediated gene expression and cancer cell proliferation . Mol Oncol , 17 ( 7 ): 1228 - 1245 . https://doi.org/10.1002/1878-0261.13438 https://doi.org/10.1002/1878-0261.13438

Quereda V , Bayle S , Vena F , et al. , 2019 . Therapeutic targeting of CDK12/CDK13 in triple-negative breast cancer . Cancer Cell , 36 ( 5 ): 545 - 558.e7 . https://doi.org/10.1016/j.ccell.2019.09.004 https://doi.org/10.1016/j.ccell.2019.09.004

Rana S , Bendjennat M , Kour S , et al. , 2019 . Selective degradation of CDK6 by a palbociclib based PROTAC . Bioorg Med Chem Lett , 29 ( 11 ): 1375 - 1379 . https://doi.org/10.1016/j.bmcl.2019.03.035 https://doi.org/10.1016/j.bmcl.2019.03.035

Řezníčková E , Krajčovičová S , Peřina M , et al. , 2022 . Modulation of FLT3-ITD and CDK9 in acute myeloid leukaemia cells by novel proteolysis targeting chimera (PROTAC) . Eur J Med Chem , 243 : 114792 . https://doi.org/10.1016/j.ejmech.2022.114792 https://doi.org/10.1016/j.ejmech.2022.114792

Riching KM , Schwinn MK , Vasta JD , et al. , 2021 . CDK family PROTAC profiling reveals distinct kinetic responses and cell cycle-dependent degradation of CDK2 . SLAS Discov , 26 ( 4 ): 560 - 569 . https://doi.org/10.1177/2472555220973602 https://doi.org/10.1177/2472555220973602

Rishfi M , Krols S , Martens F , et al. , 2023 . Targeted AURKA degradation: towards new therapeutic agents for neuroblastoma . Eur J Med Chem , 247 : 115033 . https://doi.org/10.1016/j.ejmech.2022.115033 https://doi.org/10.1016/j.ejmech.2022.115033

Robb CM , Contreras JI , Kour S , et al. , 2017 . Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC) . Chem Commun , 53 ( 54 ): 7577 - 7580 . https://doi.org/10.1039/C7CC03879H https://doi.org/10.1039/C7CC03879H

Rusan M , Li K , Li Y , et al. , 2018 . Suppression of adaptive responses to targeted cancer therapy by transcriptional repression . Cancer Discov , 8 ( 1 ): 59 - 73 . https://doi.org/10.1158/2159-8290.CD-17-0461 https://doi.org/10.1158/2159-8290.CD-17-0461

Sakamoto KM , Kim KB , Kumagai A , et al. , 2001 . Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation . Proc Natl Acad Sci USA , 98 ( 15 ): 8554 - 8559 . https://doi.org/10.1073/pnas.141230798 https://doi.org/10.1073/pnas.141230798

Sanda T , Lawton LN , Barrasa MI , et al. , 2012 . Core transcriptional regulatory circuit controlled by the TAL1 complex in human T cell acute lymphoblastic leukemia . Cancer Cell , 22 ( 2 ): 209 - 221 . https://doi.org/10.1016/j.ccr.2012.06.007 https://doi.org/10.1016/j.ccr.2012.06.007

Satyanarayana A , Kaldis P , 2009 . Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms . Oncogene , 28 ( 33 ): 2925 - 2939 . https://doi.org/10.1038/onc.2009.170 https://doi.org/10.1038/onc.2009.170

Schachter MM , Fisher RP , 2013 . The CDK-activating kinase Cdk7: taking yes for an answer . Cell Cycle , 12 ( 20 ):‍ 3239 - 3240 . https://doi.org/10.4161/cc.26355 https://doi.org/10.4161/cc.26355

Schaer DA , Beckmann RP , Dempsey JA , et al. , 2018 . The CDK4/6 inhibitor abemaciclib induces a T cell inflamed tumor microenvironment and enhances the efficacy of PD-L1 checkpoint blockade . Cell Rep , 22 ( 11 ): 2978 - 2994 . https://doi.org/10.1016/j.celrep.2018.02.053 https://doi.org/10.1016/j.celrep.2018.02.053

Scheicher R , Hoelbl-Kovacic A , Bellutti F , et al. , 2015 . CDK6 as a key regulator of hematopoietic and leukemic stem cell activation . Blood , 125 ( 1 ): 90 - 101 . https://doi.org/10.1182/blood-2014-06-584417 https://doi.org/10.1182/blood-2014-06-584417

Schweizer MT , Ha G , Gulati R , et al. , 2020 . CDK12 -mutated prostate cancer: clinical outcomes with standard therapies and immune checkpoint blockade . JCO Precis Oncol , 4 : 382 - 392 . https://doi.org/10.1200/po.19.00383 https://doi.org/10.1200/po.19.00383

Scirocchi F , Scagnoli S , Botticelli A , et al. , 2022 . Immune effects of CDK4/6 inhibitors in patients with HR + /HER2 - metastatic breast cancer: relief from immunosuppression is associated with clinical response . eBioMedicine , 79 : 104010 . https://doi.org/10.1016/j.ebiom.2022.104010 https://doi.org/10.1016/j.ebiom.2022.104010

Słabicki M , Kozicka Z , Petzold G , et al. , 2020 . The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K . Nature , 585 ( 7824 ): 293 - 297 . https://doi.org/10.1038/s41586-020-2374-x https://doi.org/10.1038/s41586-020-2374-x

Steinebach C , Ng YLD , Sosič I , et al. , 2020 . Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders . Chem Sci , 11 ( 13 ): 3474 - 3486 . https://doi.org/10.1039/D0SC00167H https://doi.org/10.1039/D0SC00167H

Su S , Yang ZM , Gao HY , et al. , 2019 . Potent and preferential degradation of CDK6 via proteolysis targeting chimera degraders . J Med Chem , 62 ( 16 ): 7575 - 7582 . https://doi.org/10.1021/acs.jmedchem.9b00871 https://doi.org/10.1021/acs.jmedchem.9b00871

Sun Y , Xue YL , Sun PK , et al. , 2023 . Discovery of the first potent, selective, and in vivo efficacious polo-like kinase 4 proteolysis targeting chimera degrader for the treatment of TRIM37 -amplified breast cancer . J Med Chem , 66 ( 12 ): 8200 - 8221 . https://doi.org/10.1021/acs.jmedchem.3c00505 https://doi.org/10.1021/acs.jmedchem.3c00505

Tang RF , Wang Z , Xiang ST , et al. , 2023 . Uncovering the kinetic characteristics and degradation preference of PROTAC systems with advanced theoretical analyses . JACS Au , 3 ( 6 ): 1775 - 1789 . https://doi.org/10.1021/jacsau.3c00195 https://doi.org/10.1021/jacsau.3c00195

Teng MX , Jiang J , He ZX , et al. , 2020 . Development of CDK2 and CDK5 dual degrader TMX‐2172 . Angew Chem Int Ed , 59 ( 33 ): 13865 - 13870 . https://doi.org/10.1002/anie.202004087 https://doi.org/10.1002/anie.202004087

Thomas KL , Bouguenina H , Miller DSJ , et al. , 2024 . Degradation by design: new cyclin K degraders from old CDK inhibitors . ACS Chem Biol , 19 ( 1 ): 173 - 184 . https://doi.org/10.1021/acschembio.3c00616 https://doi.org/10.1021/acschembio.3c00616

Tien JF , Mazloomian A , Cheng SWG , et al. , 2017 . CDK12 regulates alternative last exon mRNA splicing and promotes breast cancer cell invasion . Nucleic Acids Res , 45 ( 11 ): 6698 - 6716 . https://doi.org/10.1093/nar/gkx187 https://doi.org/10.1093/nar/gkx187

Tokarski RJ , Sharpe CM , Huntsman AC , et al. , 2023 . Bifunctional degraders of cyclin dependent kinase 9 (CDK9): probing the relationship between linker length, properties, and selective protein degradation . Eur J Med Chem , 254 : 115342 . https://doi.org/10.1016/j.ejmech.2023.115342 https://doi.org/10.1016/j.ejmech.2023.115342

Ugurlu SY , McDonald D , Enisoglu R , et al. , 2025 . MEGA PROTAC, MEGA DOCK-based PROTAC mediated ternary complex formation pipeline with sequential filtering and rank aggregation . Sci Rep , 15 : 5545 . https://doi.org/10.1038/s41598-024-83558-2 https://doi.org/10.1038/s41598-024-83558-2

Verano AL , You I , Donovan KA , et al. , 2022 . Redirecting the neo-substrate specificity of cereblon-targeting PROTACs to Helios . ACS Chem Biol , 17 ( 9 ): 2404 - 2410 . https://doi.org/10.1021/acschembio.2c00439 https://doi.org/10.1021/acschembio.2c00439

Vervoort SJ , Devlin JR , Kwiatkowski N , et al. , 2022 . Targeting transcription cycles in cancer . Nat Rev Cancer , 22 ( 1 ): 5 - 24 . https://doi.org/10.1038/s41568-021-00411-8 https://doi.org/10.1038/s41568-021-00411-8

Wander SA , Cohen O , Gong XQ , et al. , 2020 . The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor-positive metastatic breast cancer . Cancer Discov , 10 ( 8 ): 1174 - 1193 . https://doi.org/10.1158/2159-8290.CD-19-1390 https://doi.org/10.1158/2159-8290.CD-19-1390

Wang J , Zhang RG , Lin ZY , et al. , 2020 . CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer . J Hematol Oncol , 13 : 99 . https://doi.org/10.1186/s13045-020-00926-x https://doi.org/10.1186/s13045-020-00926-x

Wang K , Jiang MX , Liu HM , et al. , 2024 . Discovery of novel co-degradation CK1α and CDK7/9 PROTACs with p53 activation for treating acute myeloid leukemia . Bioorg Chem , 147 : 107319 . https://doi.org/10.1016/j.bioorg.2024.107319 https://doi.org/10.1016/j.bioorg.2024.107319

Wang LG , Shao XJ , Zhong TB , et al. , 2021 . Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy . Nat Chem Biol , 17 ( 5 ): 567 - 575 . https://doi.org/10.1038/s41589-021-00742-5 https://doi.org/10.1038/s41589-021-00742-5

Wang LG , Yang ZL , Li GC , et al. , 2023 . Discovery of small molecule degraders for modulating cell cycle . Front Med , 17 ( 5 ): 823 - 854 . https://doi.org/10.1007/s11684-023-1027-5 https://doi.org/10.1007/s11684-023-1027-5

Wang TY , Zhang YM , Chen K , et al. , 2023 . CDK4/6 nano-PROTAC enhances mitochondria-dependent photodynamic therapy and anti-tumor immunity . Nano Today , 50 : 101890 . https://doi.org/10.1016/j.nantod.2023.101890 https://doi.org/10.1016/j.nantod.2023.101890

Wang YB , Zhang TH , Kwiatkowski N , et al. , 2015 . CDK7-dependent transcriptional addiction in triple-negative breast cancer . Cell , 163 ( 1 ): 174 - 186 . https://doi.org/10.1016/j.cell.2015.08.063 https://doi.org/10.1016/j.cell.2015.08.063

Wei D , Wang HL , Zeng QH , et al. , 2021 . Discovery of potent and selective CDK9 degraders for targeting transcription regulation in triple-negative breast cancer . J Med Chem , 64 ( 19 ): 14822 - 14847 . https://doi.org/10.1021/acs.jmedchem.1c01350 https://doi.org/10.1021/acs.jmedchem.1c01350

Wei MM , Zhao R , Cao YT , et al. , 2021 . First orally bioavailable prodrug of proteolysis targeting chimera (PROTAC) degrades cyclin-dependent kinases 2/4/6 in vivo . Eur J Med Chem , 209 : 112903 . https://doi.org/10.1016/j.ejmech.2020.112903 https://doi.org/10.1016/j.ejmech.2020.112903

Weng GQ , Li D , Kang Y , et al. , 2021 . Integrative modeling of PROTAC-mediated ternary complexes . J Med Chem , 64 ( 21 ): 16271 - 16281 . https://doi.org/10.1021/acs.jmedchem.1c01576 https://doi.org/10.1021/acs.jmedchem.1c01576

Wood DJ , Endicott JA , 2018 . Structural insights into the functional diversity of the CDK‍–‍cyclin family . Open Biol , 8 ( 9 ): 180112 . https://doi.org/10.1098/rsob.180112 https://doi.org/10.1098/rsob.180112

Wu J , Yuan Y , Long Priel DA , et al. , 2021 . Phase I study of zotiraciclib in combination with temozolomide for patients with recurrent high-grade astrocytomas . Clin Cancer Res , 27 ( 12 ): 3298 - 3306 . https://doi.org/10.1158/1078-0432.CCR-20-4730 https://doi.org/10.1158/1078-0432.CCR-20-4730

Wu MF , Wang W , Mao XF , et al. , 2024 . Discovery of a potent CDKs/FLT3 PROTAC with enhanced differentiation and proliferation inhibition for AML . Eur J Med Chem , 275 : 116539 . https://doi.org/10.1016/j.ejmech.2024.116539 https://doi.org/10.1016/j.ejmech.2024.116539

Wu TZ , Zhang ZM , Gong GY , et al. , 2023 . Discovery of novel flavonoid-based CDK9 degraders for prostate cancer treatment via a PROTAC strategy . Eur J Med Chem , 260 : 115774 . https://doi.org/10.1016/j.ejmech.2023.115774 https://doi.org/10.1016/j.ejmech.2023.115774

Wu XW , Yang XB , Xiong Y , et al. , 2021 . Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders . Nat Cancer , 2 ( 4 ): 429 - 443 . https://doi.org/10.1038/s43018-021-00174-z https://doi.org/10.1038/s43018-021-00174-z

Xiao LS , Liu Y , Chen H , et al. , 2023 . Targeting CDK9 with selective inhibitors or degraders in tumor therapy: an overview of recent developments . Cancer Biol Ther , 24 ( 1 ): 2219470 . https://doi.org/10.1080/15384047.2023.2219470 https://doi.org/10.1080/15384047.2023.2219470

Xie SW , Zhu JJ , Li JD , et al. , 2023 . Small-molecule hydrophobic tagging: a promising strategy of druglike technology for targeted protein degradation . J Med Chem , 66 ( 16 ): 10917 - 10933 . https://doi.org/10.1021/acs.jmedchem.3c00736 https://doi.org/10.1021/acs.jmedchem.3c00736

Xu L , Chen Y , Mayakonda A , et al. , 2018 . Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma . Proc Natl Acad Sci USA , 115 ( 22 ): E5086 - E5095 . https://doi.org/10.1073/pnas.1712363115 https://doi.org/10.1073/pnas.1712363115

Xu XQ , Pan XH , Wang TT , et al. , 2021 . Intrinsic and acquired resistance to CDK4/6 inhibitors and potential overcoming strategies . Acta Pharmacol Sin , 42 ( 2 ): 171 - 178 . https://doi.org/10.1038/s41401-020-0416-4 https://doi.org/10.1038/s41401-020-0416-4

Yang JZ , Chang Y , Tien JCY , et al. , 2022 . Discovery of a highly potent and selective dual PROTAC degrader of CDK12 and CDK13 . J Med Chem , 65 ( 16 ): 11066 - 11083 . https://doi.org/10.1021/acs.jmedchem.2c00384 https://doi.org/10.1021/acs.jmedchem.2c00384

Yao Y , Ng JF , Park WD , et al. , 2023 . CDK7 controls E2F- and MYC-driven proliferative and metabolic vulnerabilities in multiple myeloma . Blood , 141 ( 23 ): 2841 - 2852 . https://doi.org/10.1182/blood.2022018885 https://doi.org/10.1182/blood.2022018885

Yu B , Du ZK , Zhang YM , et al. , 2022 . Small-molecule degraders of cyclin-dependent kinase protein: a review . Future Med Chem , 14 ( 3 ): 167 - 185 . https://doi.org/10.4155/fmc-2021-0154 https://doi.org/10.4155/fmc-2021-0154

Zaborowska J , Egloff S , Murphy S , 2016 . The pol II CTD: new twists in the tail . Nat Struct Mol Biol , 23 ( 9 ): 771 - 777 . https://doi.org/10.1038/nsmb.3285 https://doi.org/10.1038/nsmb.3285

Zeng YP , Xiao J , Shi L , et al. , 2025 . Discovery of 2,‍4-quinazolinedione derivatives as LC3B recruiters in the facilitation of protein complex degradations . Eur J Med Chem , 287 : 117293 . https://doi.org/10.1016/j.ejmech.2025.117293 https://doi.org/10.1016/j.ejmech.2025.117293

Zhang H , Christensen CL , Dries R , et al. , 2020 . CDK7 inhibition potentiates genome instability triggering anti-tumor immunity in small cell lung cancer . Cancer Cell , 37 ( 1 ): 37 - 54.e9 . https://doi.org/10.1016/j.ccell.2019.11.003 https://doi.org/10.1016/j.ccell.2019.11.003

Zhang HH , Pandey S , Travers M , et al. , 2018 . Targeting CDK9 reactivates epigenetically silenced genes in cancer . Cell , 175 ( 5 ): 1244 - 1258.e26 . https://doi.org/10.1016/j.cell.2018.09.051 https://doi.org/10.1016/j.cell.2018.09.051

Zhang JW , Gan YC , Li HZ , et al. , 2022 . Inhibition of the CDK2 and Cyclin A complex leads to autophagic degradation of CDK2 in cancer cells . Nat Commun , 13 : 2835 . https://doi.org/10.1038/s41467-022-30264-0 https://doi.org/10.1038/s41467-022-30264-0

Zhang ZW , Golomb L , Meyerson M , 2022 . Functional genomic analysis of CDK4 and CDK6 gene dependency across human cancer cell lines . Cancer Res , 82 ( 11 ):‍ 2171 - 2184 . https://doi.org/10.1158/0008-5472.CAN-21-2428 https://doi.org/10.1158/0008-5472.CAN-21-2428

Zhao BS , Burgess K , 2019 . PROTACs suppression of CDK4/6, crucial kinases for cell cycle regulation in cancer . Chem Commun , 55 ( 18 ): 2704 - 2707 . https://doi.org/10.1039/C9CC00163H https://doi.org/10.1039/C9CC00163H

Zheng SJ , Tan YH , Wang ZY , et al. , 2022 . Accelerated rational PROTAC design via deep learning and molecular simulations . Nat Mach Intell , 4 ( 9 ): 739 - 748 . https://doi.org/10.1038/s42256-022-00527-y https://doi.org/10.1038/s42256-022-00527-y

Zhong Y , Xu J , Cao HY , et al. , 2025 . First ATG101-recruiting small molecule degrader for selective CDK9 degradation via autophagy-lysosome pathway . Acta Pharm Sin B , 15 ( 5 ): 2612 - 2624 . https://doi.org/10.1016/j.apsb.2025.03.047 https://doi.org/10.1016/j.apsb.2025.03.047

Zhou F , Chen LY , Cao CG , et al. , 2020 . Development of selective mono or dual PROTAC degrader probe of CDK isoforms . Eur J Med Chem , 187 : 111952 . https://doi.org/10.1016/j.ejmech.2019.111952 https://doi.org/10.1016/j.ejmech.2019.111952

Zhou K , Zhuang SK , Liu FL , et al. , 2022 . Disrupting the Cdk9/Cyclin T1 heterodimer of 7SK snRNP for the Brd4 and AFF1/4 guided reconstitution of active P-TEFb . Nucleic Acids Res , 50 ( 2 ): 750 - 762 . https://doi.org/10.1093/nar/gkab1228 https://doi.org/10.1093/nar/gkab1228

Zhou YF , Wang J , Deng MF , et al. , 2019 . The peptide-directed lysosomal degradation of CDK5 exerts therapeutic effects against stroke . Aging Dis , 10 ( 5 ): 1140 - 1145 . https://doi.org/10.14336/AD.2018.1225 https://doi.org/10.14336/AD.2018.1225

Views

Downloads

CSCD

Tools

Publicity Resources

No data

Related Author

No data

Related Institution

No data

Address：Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou, China Postal code：310027
Tel：+86-571-87952783 Email：cjzhang@zju.edu.cn
Technical support is provided by Beijing Founder electronics co., LTD 京ICP备09064830号-19 京公网安备11010802024621
It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.

⁰