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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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BackgroundPROTACs: great opportunities for academia and industry
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Kannt, A., & Đikić, I. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.04.007 · Cited by 153
The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination
Jin, J., Wu, Y., Chen, J., Shen, Y., Zhang, L., Zhang, H., Chen, L., Yuan, H., Chen, H., Zhang, W., et al. (2020) · Theranostics · doi:10.7150/thno.46985 · Cited by 148
“PROTAC: PROteolysis TArgeting Chimera; pPROTAC: peptide PROTAC; POI: protein of interest; CLL: chronic lymphocytic leukemia; BTK: Bruton's tyrosine kinase; UPS: ubiquitin-proteasome system; ER: estrogen receptor; AR: androgen receptor; BRD4: bromodomain-containing protein 4; ALK: anaplastic lymphoma kinase; CDK9: cycl…”
BackgroundDiscovery of Wogonin-based PROTACs against CDK9 and capable of achieving antitumor activity
Bian, J., Ren, J., Li, Y., Wang, J., Xu, X., Feng, Y., Tang, H., Wang, Y., & Li, Z. (2018) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2018.08.028 · Cited by 140
The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells
Kurimchak, A. M., Herrera-Montávez, C., Montserrat-Sangrà, S., Araiza-Olivera, D., Hu, J., Neumann-Domer, R., Kuruvilla, M., Bellacosa, A., Testa, J. R., Jin, J., et al. (2022) · Science Signaling · doi:10.1126/scisignal.abn2707 · Cited by 136
Selective Mediator dependence of cell-type-specifying transcription
Jaeger, M. G., Schwalb, B., Mackowiak, S. D., Velychko, T., Hanzl, A., Imrichová, H., Brand, M., Agerer, B., Chorn, S., Nabet, B., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0635-0 · Cited by 140
Self-citationA potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS
Bery, N., Miller, A., & Rabbitts, T. (2020) · Nature Communications · doi:10.1038/s41467-020-17022-w · Cited by 132
Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling
You, I., Erickson, E. C., Donovan, K. A., Eleuteri, N. A., Fischer, E. S., Gray, N. S., & Toker, A. (2019) · Cell chemical biology · doi:10.1016/j.chembiol.2019.11.014 · Cited by 131
Self-citationTargeting CDK9 for Anti-Cancer Therapeutics
Mandal, R., Becker, S., & Strebhardt, K. (2021) · Cancers · doi:10.3390/cancers13092181 · Cited by 132
Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders
Hanzl, A., Casement, R., Imrichova, H., Hughes, S. J., Barone, E., Testa, A., Bauer, S., Wright, J., Brand, M., Ciulli, A., et al. (2023) · Nature Chemical Biology · doi:10.1038/s41589-022-01177-2 · Cited by 133
“Simultaneously, it led to a marked sensitization (15-fold shift in EC 50 ) to the CDK9-targeting PROTAC THAL-SNS-032 40 (Extended Data Fig.”
Self-citationSolvent-Induced Protein Precipitation for Drug Target Discovery on the Proteomic Scale
Zhang, X., Wang, Q., Li, Y., Ruan, C., Wang, S., Hu, L., & Ye, M. (2019) · Analytical Chemistry · doi:10.1021/acs.analchem.9b04531 · Cited by 119
Molecular mechanisms of thalidomide and its derivatives
Ito, T., & Handa, H. (2020) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.96.016 · Cited by 123
Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update
Wu, T., Qin, Z., Tian, Y., Wang, J., Xu, C., Li, Z., & Bian, J. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00744 · Cited by 119
Mayor-Ruiz, C., Jaeger, M. G., Bauer, S., Brand, M., Sin, C., Hanzl, A., Mueller, A. C., Menche, J., & Winter, G. E. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.07.013 · Cited by 119
Self-citationBivalent Ligands for Protein Degradation in Drug Discovery
Scheepstra, M., Hekking, K. F. W., Hijfte, L. V., & Folmer, R. H. A. (2019) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2019.01.006 · Cited by 125
“[96] Olson CM, Jiang B, Erb MA, Liang Y, Doctor ZM, Zhang Z, et al. Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation.”
BackgroundInfluentialStrategies for designing proteolysis targeting chimaeras (PROTACs)
He, S., Dong, G., Cheng, J., Wu, Y., & Sheng, C. (2022) · Medicinal Research Reviews · doi:10.1002/med.21877 · Cited by 120
“However, in some cases, selective POI ligands may not yield selective degraders.(168) In addition, reasonable adjustment of the linker length in PROTACs has an important effect on the selectivity towards homologous proteins.”
BackgroundShirasaki, R., Matthews, G. M., Gandolfi, S., de Matos Simoes, R., Buckley, D. L., Raja Vora, J., Sievers, Q. L., Brüggenthies, J. B., Dashevsky, O., Poarch, H., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108532 · Cited by 123
Self-citationA Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL
Tong, B., Spradlin, J. N., Novaes, L. F. T., Zhang, E., Hu, X., Moeller, M., Brittain, S. M., McGregor, L. M., McKenna, J. M., Tallarico, J. A., et al. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00348 · Cited by 118
Development of Small Molecule Chimeras That Recruit AhR E3 Ligase to Target Proteins
Ohoka, N., Tsuji, G., Shoda, T., Fujisato, T., Kurihara, M., Demizu, Y., & Naito, M. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00704 · Cited by 119
Development of selective mono or dual PROTAC degrader probe of CDK isoforms
Zhou, F., Chen, L., Cao, C.-G., Yu, J., Luo, X., Zhou, P., Zhao, L., Du, W., Cheng, J., Xie, Y., et al. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.111952 · Cited by 118
Qiu, X., Li, Y., Yu, B., Ren, J., Huang, H., Wang, M., Ding, H., Li, Z., Wang, J., & Bian, J. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.113091 · Cited by 121
Wang, Z., He, N., Guo, Z., Niu, C., Song, T., Guo, Y., Cao, K., Wang, A., Zhu, J., Zhang, X., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00919 · Cited by 120
Self-citationPROTAC’ing oncoproteins: targeted protein degradation for cancer therapy
Kelm, J. M., Pandey, D. S., Malin, E., Kansou, H. W., Arora, S., Kumar, R., & Gavande, N. S. (2023) · Molecular Cancer · doi:10.1186/s12943-022-01707-5 · Cited by 122
Large-scale discovery of male reproductive tract-specific genes through analysis of RNA-seq datasets
Robertson, M. J., Kent, K., Tharp, N., Nozawa, K., Dean, L., Mathew, M., Grimm, S. L., Yu, Z., Légaré, C., Fujihara, Y., et al. (2020) · BMC Biology · doi:10.1186/s12915-020-00826-z · Cited by 114
Nuclear RNA binding regulates TDP-43 nuclear localization and passive nuclear export
Duan, L., Zaepfel, B. L., Aksenova, V., Dasso, M., Rothstein, J. D., Kaláb, P., & Hayes, L. R. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111106 · Cited by 110
“To confirm that TDP-43 nuclear localization is sensitive to inhibition of mRNA synthesis and avoid off-target effects of DNA intercalation, we treated HeLa cells with NVP2, an inhibitor of CDK9-dependent RNA pol II activation (Olson et al., 2018), and monitored TDP-43 localization by immunofluorescence (IF) (Figures 1…”
MethodXie, S., Zhu, J., Li, J., Zhan, F., Yao, H., Xu, J., & Xu, S. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00736 · Cited by 111
Annual review of PROTAC degraders as anticancer agents in 2022
Wang, X., Qin, Z.-L., Li, N., Jia, M.-Q., Liu, Q.-G., Bai, Y., Song, J., Yuan, S., & Zhang, S. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116166 · Cited by 107
Development and Characterization of a Wee1 Kinase Degrader
Li, Z., Pinch, B. J., Olson, C. M., Donovan, K. A., Nowak, R. P., Mills, C. E., Scott, D. A., Doctor, Z. M., Eleuteri, N. A., Chung, M., et al. (2019) · Cell chemical biology · doi:10.1016/j.chembiol.2019.10.013 · Cited by 105
“, 2019), and selective degradation of CDK9 is possible with degraders based on a non-selective CDK inhibitor(Olson et al., 2017).”
BackgroundMethodSelf-citationSPT5 stabilization of promoter-proximal RNA polymerase II
Aoi, Y., Takahashi, Y.-H., Shah, A. P., Iwanaszko, M., Rendleman, E. J., Khan, N. H., Cho, B.-K., Goo, Y. A., Ganesan, S., Kelleher, N. L., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.08.006 · Cited by 107
Targeted protein degradation directly engaging lysosomes or proteasomes
Kim, J., Byun, I., Kim, D. Y., Joh, H., Kim, H. J., & Lee, M. J. (2024) · Chemical Society Reviews · doi:10.1039/d3cs00344b · Cited by 108
Therapeutic targeting of transcriptional cyclin-dependent kinases
Galbraith, M. D., Bender, H., & Espinosa, J. M. (2018) · Transcription · doi:10.1080/21541264.2018.1539615 · Cited by 104
“NVP-2 is an aminopyrimidine-based inhibitor developed by Novartis and was recently shown to have sub-nanomolar potency towards CDK9/CycT and good selectivity against a panel of 468 kinases (Kinomescan), with ≥ 700-fold lower activity against DYRK1B and CDK7 [82].”
BackgroundInfluentialDiscovery of potent small molecule PROTACs targeting mutant EGFR
Zhao, H., Yang, X., Lei, H., Xi, X.-X., Lu, S., Zhang, J., Xin, M., & Zhang, S. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112781 · Cited by 107
Dissecting the Pol II transcription cycle and derailing cancer with CDK inhibitors
Parua, P. K., & Fisher, R. P. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0563-4 · Cited by 105
Discovery of a large-scale, cell-state-responsive allosteric switch in the 7SK RNA using DANCE-MaP
Olson, S. W., Turner, A. W., Arney, J. W., Saleem, I., Weidmann, C. A., Margolis, D. M., Weeks, K. M., & Mustoe, A. M. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.02.009 · Cited by 101
Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action
Łukasik, P., Baranowska‐Bosiacka, I., Kulczycka, K., & Gutowska, I. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062806 · Cited by 112
Röschert, I., Poon, E., Henssen, A. G., García, H. D., Gatti, M., Giansanti, C., Jamin, Y., Ade, C. P., Gallant, P., Schülein‐Völk, C., et al. (2021) · Nature Cancer · doi:10.1038/s43018-020-00171-8 · Cited by 103
CDK9 keeps RNA polymerase II on track
Egloff, S. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03878-8 · Cited by 104
Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins
Lin, J., Jin, J., Shen, Y., Zhang, L., Gong, G., Bian, H., Chen, H., Nagle, D. G., Wu, Y., Zhang, W., et al. (2021) · Theranostics · doi:10.7150/thno.62686 · Cited by 102
PROTAC degraders as chemical probes for studying target biology and target validation
Němec, V., Schwalm, M. P., Müller, S., & Knapp, S. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00478j · Cited by 98
Critical Assessment of Targeted Protein Degradation as a Research Tool and Pharmacological Modality
Kostić, M., & Jones, L. H. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.02.006 · Cited by 100
“Bcr-Abl tyrosine kinase [24], anaplastic lymphoma kinase (ALK) [25] [26], receptor tyrosine kinases [27], and cyclin-dependent kinases like CDK4 and/or 6 [28]–[30] and CDK9 [31] [32], as well as epigenetic targets [18], [19], [33]–[35] (for an up-to date and exhaustive list of available PROTACs please refer to [36]).”
BackgroundNovel immunomodulatory drugs and neo-substrates
Gao, S., Wang, S., & Song, Y. (2020) · Biomarker Research · doi:10.1186/s40364-020-0182-y · Cited by 95
Design and Characterization of SGK3-PROTAC1, an Isoform Specific SGK3 Kinase PROTAC Degrader
Tovell, H., Testa, A., Zhou, H., Shpiro, N., Crafter, C., Ciulli, A., & Alessi, D. R. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00505 · Cited by 95
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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