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Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation
Open accessAbstract
Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We characterized NVP-2, a selective ATP-competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 degrader consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN). To our surprise, THAL-SNS-032 induced rapid degradation of CDK9 without affecting the levels of other SNS-032 targets. Moreover, the transcriptional changes elicited by THAL-SNS-032 were more like those caused by NVP-2 than those induced by SNS-032. Notably, compound washout did not significantly reduce levels of THAL-SNS-032-induced apoptosis, suggesting that CDK9 degradation had prolonged cytotoxic effects compared with CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation represents a promising strategy for converting multi-targeted inhibitors into selective degraders and reveal that kinase degradation can induce distinct pharmacological effects compared with inhibition.
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“Several mechanisms have been shown to contribute to this increase in selectivity. This includes steric incapability of some targets to form a productive ternary complex, or lack of a suitably positioned lysine residue for ubiquitination.62−69”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [64]
In the citing paper
“Similarly, because of a non-linear dependence on binding, degradation target profiles often differ vastly from parental inhibitor selectivity profiles (Olson et al., 2018)”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Olson et al., 2018
In the citing paper
“It is widely believed that degraders uncouple efficacy from target occupancy (Gadd et al., 2017; Nowak et al., 2018; Olson et al., 2018; Roy et al., 2019).”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Olson et al., 2018
In the citing paper
“Simultaneously, it led to a marked sensitization (15-fold shift in EC50) to the CDK9-targeting PROTAC THAL-SNS-03240 (Extended Data Fig. 6B and C).”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [40]
In the citing paper
“For example, selective degradation of CDK9 was achieved by converting the non-selective CDK inhibitor SNS-032 into a degrader[9].”
From Development of dual and selective degraders of cyclin-dependent kinases 4 and 6 (2019) · cites this paper as [9]
In the citing paper
“It has further been shown that PROTAC selectivity does not necessarily mimic that of its target-binding warhead, but rather depends sensitively on the linker 20, 23, 24, 33”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [24]
In the citing paper
“and can have a duration of action that extends beyond clearance and depends on the turnover rate of the protein target rather than residence time 23,24,25 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [23]
In the citing paper
“Regarding clinical applications, appropriate dosage may be an issue, as saturating doses of free PROTAC molecules can antagonize the binding of binary PROTAC-protein complexes to their ternary partner and abrogate catalytic degradation, a well-documented phenomenon known as the hook effect in cell assays 23,33,34 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [23]
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“In 2018, Olson et al. (2018) reported a CDK9 PROTAC Molecule 37 (THAL-SNS-032) through the chimeric design of a CDK inhibitor SNS-032 and thalidomide.”
Hydrophobic tagging: A promising paradigm for targeted protein degradation
Xin, L., Wang, H., Yang, M., Guo, Z., Zhu, M., Moore, T. W., Dong, C., & Zhou, H. (2025) · Cell Insight · doi:10.1016/j.cellin.2025.100295 · Cited by 10
CDK7–CDK11 axis in spliceosome regulation and pre-mRNA splicing
Rájecký, M., Gajdušková, P., Maník, P., Hluchý, M., Hegedűsová, E., Kryštofová, K., Potěšil, D., Martínková, P., Slabá, Z., Khirsariya, P., et al. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf1343 · Cited by 9
“Cells were treated with 50 nM CDK9 inhibitor NVP-2 [ 83 ] or 100 nM CDK12/13 inhibitor THZ531 [ 84 , 85 ] for 2 h and cellular fractions were analyzed as in Fig.”
Reboud‐Ravaux, M. (2021) · Biologie Aujourd hui · doi:10.1051/jbio/2021007 · Cited by 10
The potential underlying mechanism of the leukemia caused by MLL‐fusion and potential treatments
Liu, H., Lee, S., Zhang, Q., Chen, Z., & Zhang, G. (2020) · Molecular Carcinogenesis · doi:10.1002/mc.23204 · Cited by 9
The transcriptional stress response and its implications in cancer treatment
Cruz-Ruiz, S., Urióstegui-Arcos, M., & Zurita, M. (2021) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2021.188620 · Cited by 9
Shan, X., Jiang, R., Gou, D., Xiang, J., Zhou, P., Xia, J. L., Wang, K., Huang, A., Tang, N., & Huang, L. (2023) · FEBS Journal · doi:10.1111/febs.16877 · Cited by 9
Progress on Small-Molecule Proteolysis-Targeting Chimeras
Huang, W., Wang, B., Zhang, Z., Zhang, C., Zeng, S., & Shen, Z. (2019) · Future Medicinal Chemistry · doi:10.4155/fmc-2019-0161 · Cited by 10
Self-citationZhang, J., Zhang, X., Huang, H., & Ding, Y. (2020) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2020.104318 · Cited by 9
McSwiggen, D. T., Liu, H., Tan, R., Puig, S. A., Akella, L. B., Berman, R., Bretan, M., Chen, H., Darzacq, X., Ford, K., et al. (2023) · eLife · doi:10.7554/elife.93183 · Cited by 9
Bazzacco, A., Mercorelli, B., & Loregian, A. (2025) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuaf046 · Cited by 11
Eaton, J. D., Jessica Board, Davidson, L., Estell, C., & West, S. (2024) · eLife · doi:10.7554/elife.92764 · Cited by 8
“Sequencing libraries were generated using the NEBNext® Ultra™ II DNA Library Prep Kit for Illumina.”
MethodKoirala, M., & DiPaola, M. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46030111 · Cited by 8
“A subset of these inhibitors, already present in our in-house inventory and previously subjected to testing, remains actively under consideration for ongoing research initiatives [7,15,16].”
BackgroundCdk6: At the interface of Rb and p53
Nebenfuehr, S., Bellutti, F., & Sexl, V. (2018) · Molecular & Cellular Oncology · doi:10.1080/23723556.2018.1511206 · Cited by 8
“The fact that specific degraders for Cyclin-dependent kinase 9 (CDK9) have recently been developed is promising that a similar endeavour may be successful for CDK6.”
BackgroundInfluentialDevelopment of a PDEδ‐Targeting PROTACs that Impair Lipid Metabolism
Winzker, M., Friese, A., Koch, U., Janning, P., Ziegler, S., & Waldmann, H. (2019) · Angewandte Chemie · doi:10.1002/ange.201913904 · Cited by 8
Development of Protein Knockdown Technology as Emerging Drug Discovery Strategy
Ohoka, N. (2018) · YAKUGAKU ZASSHI · doi:10.1248/yakushi.18-00113 · Cited by 8
Cyclin-dependent Kinase 9 as a Potential Target for Anti-TNF-resistant Inflammatory Bowel Disease
Omer, O. S., Hertweck, A., Roberts, L. B., Lo, J. W., Clough, J., Jackson, I., Pantazi, E. D., Irving, P. M., MacDonald, T. T., Pavlidis, P., et al. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.05.011 · Cited by 7
Beltrán‐Visiedo, M., Jiménez‐Alduán, N., Díez, R., Cuenca, M., Benedi, A., del Valle, A. S., Azaceta, G., Palomera, L., Peperzak, V., Anel, A., et al. (2023) · Molecular Oncology · doi:10.1002/1878-0261.13522 · Cited by 7
“In this regard, the specific CDK9 inhibitor NVP-2 [51] was also used.”
MethodJin, Q., Harris, E. J., Myers, J., Mehmood, R., Cotton, A., Shirnekhi, H. K., Baggett, D. W., Wen, J. Q., Schild, A. B., Bhansali, R. S., et al. (2024) · Blood · doi:10.1182/blood.2024024281 · Cited by 8
T-cell acute lymphoblastic leukemia: promising experimental drugs in clinical development
Thomas, X. (2022) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2023.2161361 · Cited by 7
“THAL-SNS-032 [40] and AZD4573 [41] are novel agents that inhibit CDK9.”
BackgroundZheng, M., Zhang, X., Chen, W., Xia, F., Yang, H., Yuan, K., & Yang, P. (2024) · Future Medicinal Chemistry · doi:10.4155/fmc-2023-0259 · Cited by 7
Kumar, D., Karati, D., Mahadik, K. R., & Trivedi, P. (2022) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/1871520622666220615125826 · Cited by 7
Major Advances in Emerging Degrader Technologies
Luo, H., Wu, L., He, Y., Qin, C., & Tang, X. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.921958 · Cited by 7
“Soluble kinases such as cyclin-dependent kinase 9 (Robb et al., 2017; Bian et al., 2018; Olson et al., 2018) (CDK9) and BCR-ABL (Lai et al.”
BackgroundAksoy, O., Lind, J., Sunder-Plassmann, V., Vallet, S., & Podar, K. (2022) · Cytokine · doi:10.1016/j.cyto.2022.156062 · Cited by 8
Discovery of a Potent Degrader for Fibroblast Growth Factor Receptor 1/2
Du, G., Jiang, J., Wu, Q., Henning, N. J., Donovan, K. A., Yue, H., Che, J., Lu, W., Fischer, E. S., Bardeesy, N. M., et al. (2021) · Angewandte Chemie · doi:10.1002/ange.202101328 · Cited by 7
Self-citationResearch progress on exosomes from different sources in osteoarthritis and cartilage injury
Yang, Z., Deng, Z., Gao, W., Zhang, W., Fan, X., Su, K., & Liu, Z. (2025) · Journal of Orthopaedic Surgery and Research · doi:10.1186/s13018-025-06000-x · Cited by 6
“CDK9, a key regulator of cell proliferation, plays a critical role in the transcriptional process mediated by RNA polymerase II, particularly in cellular growth [72].”
Beyond Inhibition: Recent Advances of Heterobifunctional Molecules Targeting CDK9
Yin, J., Zhang, N., Wang, T., & Zhang, X. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c02127 · Cited by 6
Wu, T., Yu, B., Gong, W., Zhang, J., Yu, S., Tian, Y., Zhao, T., Li, Z., Wang, J., & Bian, J. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115711 · Cited by 6
Therapeutic Discovery for Chromatin Complexes: Where Do We Stand?
Owens, D. D. G., Maitland, M. E. R., Arrowsmith, C. H., & Baršytė-Lovejoy, D. (2024) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-062822-110356 · Cited by 7
Ectopic expression of testis-specific transcription elongation factor in driving cancer
Zheng, B., Iwanaszko, M., Soliman, S. H. A., Ishi, Y., Gold, S. R., Qiu, R., Howard, B. C., Das, M., Zhao, Z., Hashizume, R., et al. (2025) · Science Advances · doi:10.1126/sciadv.ads4200 · Cited by 6
He, F., Wang, C., Yin, C., Li, C., Zhao, S., Wu, Z., Hu, H., & Fang, M. (2022) · Arabian Journal of Chemistry · doi:10.1016/j.arabjc.2022.104039 · Cited by 6
Khan, M. Z. I., Nazli, A., Pan, Y., & Chen, J. (2022) · Current Medicinal Chemistry · doi:10.2174/0929867329666220803112409 · Cited by 7
Selective CDK9 Degradation Using a Proteolysis-Targeting Chimera (PROTAC) Strategy
Mallareddy, J. R., Singh, S., Boghean, L., & Natarajan, A. (2021) · Future Medicinal Chemistry · doi:10.4155/fmc-2021-0220 · Cited by 6
Pearson, A. D. J., Chi, S. N., Laetscht, T. W., Marshall, L. V., Raetz, E. A., George, R. E., Chesler, L., Karres, D., Scobie, N., Knoderer, H. M., et al. (2025) · European Journal of Cancer · doi:10.1016/j.ejca.2025.115629 · Cited by 5
Harnessing Chimeric Degrader Technologies for Antimicrobial Innovation
Poddar, S. K., Dey, K., & Zheng, G. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c01479 · Cited by 5
Gajdušková, P., Mozos, I. R. D. L., Hluchý, M., Myšková, A., Zábrady, K., Maník, P., Dragišić, N., Hanáková, K., Potěšil, D., Bologna, S., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-71119-2 · Cited by 8
“…Ser7 in the CTD was reduced upon CDK7 inhibition 84 – 86 ; phosphorylation of Thr806 in SPT5 and also in the CTD of RNAPII were decreased after CDK9 inhibition 80,87,88 , and modest changes in phosphorylation of Ser2and Ser7weredetected upon longer ( ≥ 1 h) CDK12/ 13 inhibition 78,81,89 – 95 (Fig.”
Liu, R. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.05.114 · Cited by 5
PROTACs in platelets: emerging antithrombotic strategies and future perspectives
Trory, J. S., Vautrinot, J., May, C., & Hers, I. (2024) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000846 · Cited by 5
Metadata
- Authors
- Olson, C. M., Jiang, B., Erb, M. A., Liang, Y., Doctor, Z. M., Zhang, Z., Zhang, T., Kwiatkowski, N., Boukhali, M., Green, J. L., Haas, W., Nomanbhoy, T., Fischer, E. S., Young, R. A., Bradner, J. E., Winter, G. E., & Gray, N. S.
- Affiliations
- Harvard University (US)
- California Sea Grant (US)
- Whitehead Institute for Biomedical Research (US)
- Corresponding author
- Gray, Nathanael S
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2017-12-18
- Volume
- 14
- Issue
- 2
- Pages
- 163-170
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC5912898
- OpenAlex
- W2781383440
- Cited by
- 552
- References
- 49
- Citations by year
- 2026: 41 · 2025: 78 · 2024: 71 · 2023: 63 · 2022: 69 · 2021: 77 · 2020: 77 · 2019: 51 · 2018: 24 · 2017: 1
- FWCI
- 17.42
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion)
- PMC
- Funders
- National Cancer Institute (R01CA179483, R01CA218278)
- National Institute of General Medical Sciences (T32GM007753)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- CDK9, transcription elongation, CDK9 inhibitor, SNS-032, cereblon, E3 ubiquitin ligase, apoptosis, transcriptional dysregulation, cancer therapy
- MeSH terms
- Humans, Ligands, Oxazoles, Peptide Hydrolases, Phosphorylation, Protein Binding, Protein Conformation, Thalidomide, Thiazoles, Apoptosis, Crystallography, X-Ray, Inhibitory Concentration 50, Proteomics, Cyclin-Dependent Kinase 9, Ubiquitin-Protein Ligases, Cell Line, Tumor, Protein Kinase Inhibitors, Adaptor Proteins, Signal Transducing, Cell Proliferation
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