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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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CDK9 interacts with a RanGTP–importin-β complex to regulate erythroid enucleation
Newton, L. M., Lim, K. Y. B., Abeid, D. Y., Wölwer, C. B., Johnson, C. J., Russell, S. M., Hawkins, E. D., & Humbert, P. O. (2026) · Journal of Cell Science · doi:10.1242/jcs.264385 · Cited by 1
“Atuveiclib (BAY 1143572) (Lücking et al., 2017) and the thalidomide-conjugate PROTAC degrader THAL-SNS-032 (Olson et al., 2017) both arrested enucleation compared to the vehicle (DMSO) control (Fig.”
PROTACs in cancer therapy: targeted degradation of GPX4, PARP and epigenetic regulators
Periyasamy, S., Jarrett, T., Truong, J., & Skouta, R. (2026) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2026.2636394 · Cited by 2
Wei, N., Thielen, N., Mohammadi, M., Bhat, M. A., Li, T., Sun, Y., Kitamura, S., Chu, E., & Kuang, C. (2026) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2026.05.008 · Cited by 2
CDK9 and hematologic malignancies: pioneering novel therapeutic approaches
Raufi, H., Zahmatkesh, P., Safaei, S., Bahadori, A., & Solali, S. (2026) · Clinical and Experimental Medicine · doi:10.1007/s10238-026-02141-3 · Cited by 1
“Furthermore, NVP-2 has been shown to decrease overall mRNA levels in MOLT4 cells while promoting RNA polymerase II accumulation near promoter regions [119].”
The synthetic landscape of cereblon (CRBN) binders: from thalidomide to emerging chemotypes
Rafael, S., Sánchez, C., Whelan, R., Harris, C., Verdaguer, X., Mayor‐Ruiz, C., & Riéra, A. (2026) · Chemical Society Reviews · doi:10.1039/d6cs00247a · Cited by 1
PROTACs in Treatment of Glioma
Kumar, S., & Maharshi, V. (2024) · Springer eBooks · doi:10.1007/978-981-97-5077-1_15 · Cited by 1
Thomas, X. (2025) · Oncology and Therapy · doi:10.1007/s40487-025-00339-1 · Cited by 1
“Other CDK9 inhibitors of potential interest include THAL-SNS-032 [24] and AZD4573 [25].”
Structural and Biophysical Principles of Degrader Ternary Complexes
Zollman, D., & Ciulli, A. (2020) · Royal Society of Chemistry eBooks · doi:10.1039/9781839160691-00014 · Cited by 3
Olson, S. W., Turner, A. W., Arney, J. W., Saleem, I., Weidmann, C. A., Margolis, D. M., Weeks, K. M., & Mustoe, A. M. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.09.16.460563 · Cited by 1
“Defining 7SK regulatory mechanisms will both illuminate fundamental aspects of transcriptional control and also inform ongoing efforts to inhibit transcription in disease settings, especially cancer (Olson et al., 2018), and, conversely, to activate transcription as part of “kick-and-kill” HIV cure strategies (Richman…”
BackgroundTrivalent PROTACs Enhance Protein Degradation Through Cooperativity and AvidityPreprint
Imaide, S., Riching, K. M., Vetma, V., Whitworth, C., Hughes, S. J., Trainor, N. B., Mahan, S. D., Murphy, N., Chan, K.-H., Testa, A., et al. (2020) · ChemRxiv · doi:10.26434/chemrxiv.13218695 · Cited by 1
WITHDRAWN: Targeted protein degradation: A promising approach for cancer treatment
Khan, M. Z. I., Nazli, A., Naz, I., Khan, D., Haq, I., & Chen, J. (2023) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2023.09.004 · Cited by 1
RetractedTargeted Degradation of CDK9 Potently Disrupts the MYC Transcriptional NetworkPreprint
Toure, M. A., Motoyama, K., Xiang, Y., Urgiles, J., Kabinger, F., Koglin, A.-S., Iyer, R. S., Gagnon, K., Kumar, A., Ojeda, S., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.14.593352 · Cited by 1
“Several CDK9 degraders have been reported over the last few years 10–12 that effectively degrade the kinase.”
BackgroundSun, R., & Fisher, R. P. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.25.605161 · Cited by 1
Dehmer, M., Gallant, P., Herold, S., Cossa, G., Conte, F., Köster, J., Sauer, F., Schülein‐Völk, C., Ade, C. P., Vidal, R. S., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.29.605622 · Cited by 1
RNA-mediated MYC multimerization suppresses innate immune signalingPreprint
Uhl, L., Aziba, A., Löbbert, S., Russell, T. J., Kannan, T., Valanju, O. R., Schülein-Völk, C., de Martines, T., Montesinos, F., Bolz, M., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.06.627168 · Cited by 1
Torres‐Ayuso, P., & Brognard, J. (2025) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2025.2500418 · Cited by 1
“Thus, PROTACs are likely efficient at substoichiometric concentrations [32,33].”
Identification of human RNA Polymerase II interactors at early stages of transcriptionPreprint
Ozer, A., Kang, J. J., Tang, Y., Yugandhar, K., Sun, Y., DeBerardine, M., Omar, K., Lis, J. T., & Yu, H. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.08.681243 · Cited by 1
“NVP-2, a specific P-TEFb (CDK9/CYCT1 heterodimeric complex) inhibitor 58 , can effectively halt the release of paused Pol II into productive elongation, while already elongating Pol IIs continue transcription more or less unaffected.”
Cyclin-dependent kinase 2 (Cdk2) controls phosphatase-regulated signaling and function in plateletsPreprint
Woods, P. R., Hood, B. L., Shiva, S., Conrads, T. P., Suchko, S., & Steinman, R. A. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.05.31.126953
“Additional cdk2 inhibitors BMS26524644; and SNS-03245 were used to reduce the likelihood of that inhibitor effects were off target.”
MethodInfluentialReversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs
Trauner, D. H., & Arp, C. J. (2020) · Synfacts · doi:10.1055/s-0040-1707494
Blocking the Enablers: Selective Inhibition of CDK9 Reins in an Unchecked Master Regulator
Ansari, A. Z. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.01.022
Targeting MDM2, the antagonist of the tumor suppressor p53
Sriraman, A. (2018) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-7056
Faculty Opinions recommendation of Emerging new concepts of degrader technologies.
Bernstein, P. R. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.737971820.793576450
Synthetic Small Molecules in Prostate Cancer Therapeutics
Eldhose, B., & Bowling, G. C. (2021) · Handbook of Oxidative Stress in Cancer: Therapeutic Aspects · doi:10.1007/978-981-16-1247-3_225-1
Synthetic Small Molecules in Prostate Cancer Therapeutics
Eldhose, B., & Bowling, G. C. (2022) · Handbook of Oxidative Stress in Cancer: Therapeutic Aspects · doi:10.1007/978-981-16-5422-0_225
Xu, X., Eshima, S., Kato, S., Fisher, D. E., Sakurai, H., Hayakawa, Y., & Yokoyama, S. (2023) · doi:10.1158/1535-7163.c.6538327.v1
Xu, X., Eshima, S., Kato, S., Fisher, D. E., Sakurai, H., Hayakawa, Y., & Yokoyama, S. (2023) · doi:10.1158/1535-7163.c.6538327
Lin, X., Zheng, Z., Liu, J., Chen, Y., Ding, J., Hu, G., Hu, Y.-H., Liu, S., Luo, W., Xia, N., et al. (2023) · doi:10.1158/2326-6066.c.6550326
Itkonen, H. M., Poulose, N., Steele, R. E., Martin, S. E. S., Levine, Z. G., Duveau, D. Y., Carelli, R., Singh, R., Urbanucci, A., Loda, M. F., et al. (2023) · doi:10.1158/1541-7786.22527036
Itkonen, H. M., Poulose, N., Steele, R. E., Martin, S. E. S., Levine, Z. G., Duveau, D. Y., Carelli, R., Singh, R., Urbanucci, A., Loda, M. F., et al. (2023) · doi:10.1158/1541-7786.22527036.v1
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Qiu, Z., Zhao, L., Shen, J., Liang, Z., Wu, Q., Yang, K., Min, L., Gimple, R. C., Yang, Q., Bhargava, S., et al. (2023) · doi:10.1158/2159-8290.22541297
New Therapeutic Chemical Modalities: Compositions, Modes-of-action, and Drug Discovery
Valeur, E. (2023) · Royal Society of Chemistry eBooks · doi:10.1039/9781788018982-00911
Eaton, J. D., Jessica Board, Davidson, L., Estell, C., & West, S. (2024) · eLife · doi:10.7554/elife.92764.1
Eaton, J. D., Jessica Board, Davidson, L., Estell, C., & West, S. (2024) · eLife · doi:10.7554/elife.92764.2
PROTACs of cyclin-dependent kinases
Veselá, D., Řezníčková, E., Mik, V., & Jorda, R. (2024) · Annual reports in medicinal chemistry · doi:10.1016/bs.armc.2024.10.003
RNA polymerase II O-GlcNAcylation promotes nuclear entry to drive transcriptionPreprint
Pallasaho, S., Lu, X., Gondane, A., & Itkonen, H. M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.03.18.643968
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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