Differential activity of specific inhibitors of transcription regulating cyclin-dependent kinases in thyroid cancer cells

in Endocrine-Related Cancer
Authors:
Neel Rajan Department of Molecular Medicine and Therapeutics, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio, USA
The Ohio State University, Columbus, Ohio, USA

Search for other papers by Neel Rajan in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-4791-9546
,
Tilak Khanal Department of Molecular Medicine and Therapeutics, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio, USA
The Ohio State University, Columbus, Ohio, USA

Search for other papers by Tilak Khanal in
Current site
Google Scholar
PubMed Close
,
Amy Adik Department of Molecular Medicine and Therapeutics, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio, USA
The Ohio State University, Columbus, Ohio, USA

Search for other papers by Amy Adik in
Current site
Google Scholar
PubMed Close
,
Anisley Valenciaga Department of Molecular Medicine and Therapeutics, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio, USA
The Ohio State University, Columbus, Ohio, USA

Search for other papers by Anisley Valenciaga in
Current site
Google Scholar
PubMed Close
,
Akanksha Nigam Department of Molecular Medicine and Therapeutics, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio, USA
The Ohio State University, Columbus, Ohio, USA

Search for other papers by Akanksha Nigam in
Current site
Google Scholar
PubMed Close
,
Sandya Liyanarachchi Department of Molecular Medicine and Therapeutics, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio, USA
The Ohio State University, Columbus, Ohio, USA

Search for other papers by Sandya Liyanarachchi in
Current site
Google Scholar
PubMed Close
, and
Matthew D Ringel Department of Molecular Medicine and Therapeutics, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio, USA
The Ohio State University, Columbus, Ohio, USA

Search for other papers by Matthew D Ringel in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0001-8672-3266

Correspondence should be addressed to M D Ringel: matthew.ringel@osumc.edu

(N Rajan and T Khanal contributed equally to this work)

DOI:
https://doi.org/10.1530/ERC-24-0124
Volume/Issue:
Volume 32: Issue 6
Article Type:
Research Article
Article ID:
e240124
Online Publication Date:
29 May 2025
Copyright:
© the author(s) 2025
Restricted access
Rent on DeepDyve

Sign up for journal news

‘Superenhanced’ transcription of oncogenes by aberrant looping of upstream enhancer elements to transcriptional regulatory regions is a mechanism of oncogene overexpression. Non-selective cyclin-dependent kinase inhibitors (CDKi) that target transcriptionally regulatory CDKs, including CDK7, 9, 12 and 13, reduce mRNA levels of super-enhanced oncogenes and have activity against thyroid cancer cells. We hypothesized that more specific inhibitors of CDKs would have differential activities in thyroid cancer cells and may be suitable for further studies. We selected thyroid cancer cell lines with a variety of genetic drivers for initial screening studies with CDK7/12/13 (THZ1) and CDK9 (AZD4573) inhibitors. IC50 values ranged from 5 to 100 nM for THZ1 for all cell lines and six of eight cell lines for AZD4573, with inhibition of RNAPII phosphorylation and evidence of reduced cell migration. Four thyroid cancer cell lines with common driver mutations, including 8505C (BRAFV600E), BCPAP (BRAFV600E), TPC1 (RET fusion) and FTC133 (PTEN null), were selected for detailed studies with more specific inhibitors. In these cells, the CDK 12/13 inhibitor (SR-4835) and AZD4573 were more effective than the specific CDK7 inhibitor YKL-5-124 at reducing cell survival, migration and proliferation, and at inducing apoptosis. Treatment with SR-4835 was the most potent, induced DNA damage and resulted in cyclin K loss. Combined reduction in CDK12/13 levels with siRNA reduced RNAPII phosphorylation. These data suggest that specific inhibitors of CDK12/13 may be particularly active in thyroid cancer cell lines; further studies evaluating their efficacy are warranted in thyroid cancer.

Supplementary Materials

Endocrine-Related Cancer is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 34 34 17
PDF Downloads 41 41 23

 

  • Collapse
  • Expand
Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© the author(s) 2025
Article ID:
e240124
Received Date:
10 Apr 2024
Rev-recd:
07 Mar 2025
Accepted Date:
29 Apr 2025
Print Publication Date:
01 Jun 2025
Online Publication Date:
29 May 2025
Keywords:
CDK7; CDK9; CDK 12; CDK13; cancer-specific transcriptional control

  • Bai N , Xia F , Wang W , et al. 2020 CDK12 promotes papillary thyroid cancer progression through regulating the c-myc/β-catenin pathway. J Cancer 11 4308–4315. (https://doi.org/10.7150/jca.42849)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bartkowiak B , Yan CM , Soderblom EJ , et al. 2019 CDK12 activity-dependent phosphorylation events in human cells. Biomolecules 9 634. (https://doi.org/10.3390/biom9100634)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bautista L , Knippler CM & Ringel MD 2020 p21-Activated kinases in thyroid cancer. Endocrinology 161 bqaa105. (https://doi.org/10.1210/endocr/bqaa105)

  • Blazek D , Kohoutek J , Bartholomeeusen K , et al. 2011 The cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes Dev 25 2158–2172. (https://doi.org/10.1101/gad.16962311)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Boucai L , Zafereo M & Cabanillas ME 2024 Thyroid cancer: a review. JAMA 331 425–435. (https://doi.org/10.1001/jama.2023.26348)

  • Bradner JE 2014 From transcriptional regulation to drugging the cancer epigenome. Genome Med 6 123. (https://doi.org/10.1186/s13073-014-0123-1)

  • Bradner JE , Hnisz D & Young RA 2017 Transcriptional addiction in cancer. Cell 168 629–643. (https://doi.org/10.1016/j.cell.2016.12.013)

  • Buratowski S 2009 Progression through the RNA polymerase II CTD cycle. Mol Cell 36 541–546. (https://doi.org/10.1016/j.molcel.2009.10.019)

  • Cao X , Dang L , Zheng X , et al. 2019 Targeting super-enhancer-driven oncogenic transcription by CDK7 inhibition in anaplastic thyroid carcinoma. Thyroid 29 809–823. (https://doi.org/10.1089/thy.2018.0550)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chang Y , Wang X , Yang J , et al. 2024 Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition. Cell Rep Med 5 101752. (https://doi.org/10.1016/j.xcrm.2024.101752)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chirackal Manavalan AP , Pilarova K , Kluge M , et al. 2019 CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes. EMBO Rep 20 e47592. (https://doi.org/10.15252/embr.201847592)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cidado J , Boiko S , Proia T , et al. 2020 AZD4573 is a highly selective CDK9 inhibitor that suppresses MCL-1 and induces apoptosis in hematologic cancer cells. Clin Cancer Res 26 922–934. (https://doi.org/10.1158/1078-0432.ccr-19-1853)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Doolittle WKL , Zhao L & Cheng SY 2022 Blocking CDK7-mediated NOTCH1-cMYC signaling attenuates cancer stem cell activity in anaplastic thyroid cancer. Thyroid 32 937–948. (https://doi.org/10.1089/thy.2022.0087)

    • PubMed
    • Search Google Scholar
    • Export Citation

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

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Enomoto K , Zhu X , Park S , et al. 2017 Targeting MYC as a therapeutic intervention for anaplastic thyroid cancer. J Clin Endocrinol Metab 102 2268–2280. (https://doi.org/10.1210/jc.2016-3771)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Greber BJ , Toso DB , Fang J , et al. 2019 The complete structure of the human TFIIH core complex. Elife 8 1–29. (https://doi.org/10.7554/elife.44771)

  • Gressel S , Schwalb B & Cramer P 2019 The pause-initiation limit restricts transcription activation in human cells. Nat Commun 10 3603–3612. (https://doi.org/10.1038/s41467-019-11536-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Guo T , Liu DF & Peng SH 2022 CDK9 is up-regulated and associated with prognosis in patients with papillary thyroid carcinoma. Medicine 101 e28309. (https://doi.org/10.1097/md.0000000000028309)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hamidi S , Hofmann MC , Iyer PC , et al. 2023 Review article: new treatments for advanced differentiated thyroid cancers and potential mechanisms of drug resistance. Front Endocrinol 14 1176731. (https://doi.org/10.3389/fendo.2023.1176731)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Haugen BR 2016 2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: what is new and what has changed? ACS Journals 123 372–381. (https://doi.org/10.1002/cncr.30360)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Houles T , Lavoie G , Nourreddine S , et al. 2022 CDK12 is hyperactivated and a synthetic-lethal target in BRAF-mutated melanoma. Nat Commun 13 6457. (https://doi.org/10.1038/s41467-022-34179-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Holm S 1979 A simple sequentially rejective multiple test procedure. Scand J Stat 6 65–70. (https://www.jstor.org/stable/4615733)

  • 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)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jiang B , Gao Y , Che J , et al. 2021 Discovery and resistance mechanism of a selective CDK12 degrader. Nat Chem Biol 17 675–683. (https://doi.org/10.1038/s41589-021-00765-y)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kelley JR , Dimitrova E , Maciuszek M , et al. 2024 The PNUTS phosphatase complex controls transcription pause release. Mol Cell 84 4843–4861 e8. (https://doi.org/10.1016/j.molcel.2024.10.045)

    • PubMed
    • Search Google Scholar
    • Export Citation

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

    • PubMed
    • Search Google Scholar
    • Export Citation

  • 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)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Krishnamurthy S & Hampsey M 2009 Eukaryotic trancription initiation. Curr Biol 19 153–156. (https://doi.org/10.1016/j.cub.2008.11.052)

  • Landa I , Pozdeyev N , Korch C , et al. 2019 Comprehensive genetic characterization of human thyroid cancer cell lines: a validated panel for preclinical studies. Clin Cancer Res 25 3141–3151. (https://doi.org/10.1158/1078-0432.CCR-18-2953)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Larochelle S , Amat R , Glover-Cutter K , et al. 2012 Cyclin-dependent kinase control of the initiation-to-elongation switch of RNA polymerase II. Nat Struct Mol Biol 19 1108–1115. (https://doi.org/10.1038/nsmb.2399)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lee WK & Cheng SY 2021 Targeting transcriptional regulators for treatment of anaplastic thyroid cancer. J Cancer Metastasis Treat 7 27. (https://doi.org/10.20517/2394-4722.2021.58)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li H , Wang J , Yi Z , et al. 2021 CDK12 inhibition enhances sensitivity of HER2+ breast cancers to HER2-tyrosine kinase inhibitor via suppressing PI3K/AKT. Eur J Cancer 145 92–108. (https://doi.org/10.1016/j.ejca.2020.11.045)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li Z , Li X , Seebacher NA , et al. 2024 CDK12 is a promising therapeutic target for the transcription cycle and DNA damage response in metastatic osteosarcoma. Carcinogenesis 45 786–798. (https://doi.org/10.1093/carcin/bgae051)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liu H , Shin SH , Chen H , et al. 2020 CDK12 and PAK2 as novel therapeutic targets for human gastric cancer. Theranostics 10 6201–6215. (https://doi.org/10.7150/thno.46137)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lopes-Ventura S , Pojo M , Matias AT , et al. 2019 The efficacy of HRAS and CDK4/6 inhibitors in anaplastic thyroid cancer cell lines. J Endocrinol Investig 42 527–540. (https://doi.org/10.1007/s40618-018-0947-4)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Loven J , Hoke HA , Lin CY , et al. 2013 Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153 320–334. (https://doi.org/10.1016/j.cell.2013.03.036)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lu H , Sun D , Wang Z , et al. 2025 Design, synthesis, and biological evaluation of novel orally available covalent CDK12/13 dual inhibitors for the treatment of tumors. J Med Chem 68 4148–4167. (https://doi.org/10.1021/acs.jmedchem.4c01616)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mccarty SK , Saji M , Zhang X , et al. 2010 Group I p21-activated kinases regulate thyroid cancer cell migration and are overexpressed and activated in thyroid cancer invasion. Endocr Relat Cancer 17 989–999. (https://doi.org/10.1677/erc-10-0168)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mounika P , Gurupadayya B , Kumar HY , et al. 2023 An overview of CDK enzyme inhibitors in cancer therapy. Curr Cancer Drug Targets 23 603–619. (https://doi.org/10.2174/1568009623666230320144713)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nabhan F , Dedhia PH & Ringel MD 2021 Thyroid cancer, recent advances in diagnosis and therapy. Int J Cancer 149 984–992. (https://doi.org/10.1002/ijc.33690)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nakamura Y , Hattori N , Iida N , et al. 2017 Targeting of super-enhancers and mutant BRAF can suppress growth of BRAF-mutant colon cancer cells via repression of MAPK signaling pathway. Cancer Lett 402 100–109. (https://doi.org/10.1016/j.canlet.2017.05.017)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Niu T , Li K , 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)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Olson CM , Liang Y , Leggett A , et al. 2019 Development of a selective CDK7 covalent inhibitor reveals predominant cell-cycle phenotype. Cell Chem Biol 26 792–803 e10. (https://doi.org/10.1016/j.chembiol.2019.02.012)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pereira M , Williams VL , Johnson JH , et al. 2020 Thyroid cancer incidence trends in the United States: association with changes in professional guidelines recommendations. Thyroid 33 1132–1140. (https://doi.org/10.1089/thy.2019.0415)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pinto N , Prokopec SD , Ghasemi F , et al. 2020 Flavopiridol causes cell cycle inhibition and demonstrates anti-cancer activity in anaplastic thyroid cancer models. PLoS One 15 e0239315. (https://doi.org/10.1371/journal.pone.0239315)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pott S & Lieb JD 2014 What are super-enhancers? Nat Genet 47 8–12. (https://doi.org/10.1038/ng.3167)

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

    • PubMed
    • Search Google Scholar
    • Export Citation

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

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ringel MD 2021 New horizons: emerging therapies and targets in thyroid cancer. J Clin Endocrinol Metab 106 e382–e388. (https://doi.org/10.1210/clinem/dgaa687)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ritz C , Baty F , Streibig CJ , et al. 2015 Dose-response analysis using R. PLoS One 10 e0146021. (https://doi.org/10.1371/journal.pone.0146021)

  • Rojas P , Wang J , Guglielmi G , et al. 2024 Genome-wide identification of replication fork stalling/pausing sites and the interplay between RNA Pol II transcription and DNA replication progression. Genome Biol 25 126. (https://doi.org/10.1186/s13059-024-03278-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Roy R , Gampa SC & Garimella SV 2024 Role of specific CDKs in regulating DNA damage repair responses and replication stress. Curr Opin Pharmacol 79 102485. (https://doi.org/10.1016/j.coph.2024.102485)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sakr HI , Chute DJ , Nasr C , et al. 2017 cMYC expression in thyroid follicular cell-derived carcinomas: a role in thyroid tumorigenesis. Diagn Pathol 12 71. (https://doi.org/10.1186/s13000-017-0661-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Schmitz M , Kaltheuner IH , Anand K , et al. 2024 The reversible inhibitor SR-4835 binds Cdk12/cyclin K in a noncanonical G-loop conformation. J Biol Chem 300 105501. (https://doi.org/10.1016/j.jbc.2023.105501)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Siegel RL , Giaquinto AN & Jemal A 2024 Cancer statistics, 2024. CA Cancer J Clin 74 12–49. (https://doi.org/10.3322/caac.21820)

  • Steurer B , Janssens RC , Geverts B , et al. 2018 Live-cell analysis of endogenous GFP-RPB1 uncovers rapid turnover of initiating and promoter-paused RNA polymerase II. Proc Natl Acad Sci U S A 115 4368–4376. (https://doi.org/10.1073/pnas.1717920115)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Steurer B , Janssens RC , Geijer ME , et al. 2022 DNA damage-induced transcription stress triggers the genome-wide degradation of promoter-bound pol II. Nat Commun 13 3624. (https://doi.org/10.1038/s41467-022-31329-w)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sun Y , Zhang Y , Schultz CW , et al. 2022 CDK7 inhibition synergizes with topoisomerase I inhibition in small cell lung cancer cells by inducing ubiquitin-mediated proteolysis of RNA polymerase II. Mol Cancer Ther 21 1430–1438. (https://doi.org/10.1158/1535-7163.mct-21-0891)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tien JC , Luo J , Chang Y , et al. 2024 CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13. Cell Rep Med 5 101758. (https://doi.org/10.1016/j.xcrm.2024.101758)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Valenciaga A , Saji M , Yu L , et al. 2018 Transcriptional targeting of oncogene addiction in medullary thyroid cancer. JCI Insight 3 1–20. (https://doi.org/10.1172/jci.insight.122225)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Vasko V , Espinosa AV , Scouten W , et al. 2006 Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion. Proc Natl Acad Sci U S A 104 2803–2808. (https://doi.org/10.1073/pnas.0610733104)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wong K , Di Cristofano F , Ranieri M , et al. 2019 PI3K/mTOR inhibition potentiates and extends palbociclib activity in anaplastic thyroid cancer. Endocr Relat Cancer 26 425–436. (https://doi.org/10.1530/erc-19-0011)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wu W , Yu S & Yu X 2023 Transcription-associated cyclin-dependent kinase 12 (CDK12) as a potential target for cancer therapy. Biochim Biophys Acta Rev Cancer 1878 188842. (https://doi.org/10.1016/j.bbcan.2022.188842)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wu Z , Zhang W , Chen L , et al. 2024 CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in colorectal cancer. Pharmacol Res 201 107097. (https://doi.org/10.1016/j.phrs.2024.107097)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Xiao Y & Dong J 2023 Coming of age: targeting cyclin K in cancers. Cells 12 2044. (https://doi.org/10.3390/cells12162044)

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

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang T , Kwiatkowski N , Olson CM , et al. 2016 Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat Chem Biol 12 876–884. (https://doi.org/10.1038/nchembio.2166)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang M , Zhang L , Hei R , et al. 2021 CDK inhibitors in cancer therapy, an overview of recent development. Am J Cancer Res 11 1913–1935.

  • Zhang Y , Shan L , Tang W , et al. 2024 Recent discovery and development of inhibitors that target CDK9 and their therapeutic indications. J Med Chem 67 5185–5215. (https://doi.org/10.1021/acs.jmedchem.4c00312)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zheng M , Zhang XY , Chen W , et al. 2024 Molecules inducing specific cyclin-dependent kinase degradation and their possible use in cancer therapy. Future Med Chem 16 369–388. (https://doi.org/10.4155/fmc-2023-0259)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhou L , Zhou K , Chang Y , et al. 2024 Discovery of ZLC491 as a potent, selective, and orally bioavailable CDK12/13 PROTAC degrader. J Med Chem 67 18247–18264. (https://doi.org/10.1021/acs.jmedchem.4c01596)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhu X , Holmsen E , Park S , et al. 2018 Synergistic effects of BET and MEK inhibitors promote regression of anaplastic thyroid tumors. Oncotarget 9 35408–35421. (https://doi.org/10.18632/oncotarget.26253)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhu X , Park S , Lee WK , et al. 2019 Potentiated anti-tumor effects of BETi by MEKi in anaplastic thyroid cancer. Endocr Relat Cancer 26 739–750. (https://doi.org/10.1530/erc-19-0107)

    • PubMed
    • Search Google Scholar
    • Export Citation