The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
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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BindingDB Entry 50017954: PROTACs to address the challenges facing small molecule inhibitors.
BindingDB (2023) · UC San Diego · doi:10.7270/q2p55sm1
BindingDB (2025) · UC San Diego · doi:10.7270/q2ws8zww
BindingDB Entry 50019525: PROTACS: A technology with a gold rush-like atmosphere.
BindingDB (2024) · UC San Diego · doi:10.7270/q2hq4488
BindingDB Entry 50016810: 3,5,7-Substituted Pyrazolo[4,3-
BindingDB (2023) · UC San Diego · doi:10.7270/q26114cs
BindingDB Entry 50018659: Developments of CRBN-based PROTACs as potential therapeutic agents.
BindingDB (2024) · UC San Diego · doi:10.7270/q27948wc
BindingDB (2025) · UC San Diego · doi:10.7270/q2vh5th3
BindingDB Entry 50010375: Discovery and SARs of 5-Chloro-
BindingDB (2021) · UC San Diego · doi:10.7270/q2n87f9b
BindingDB Entry 50021665: The application of PROTAC in HDAC.
BindingDB (2025) · UC San Diego · doi:10.7270/q2474gjr
BindingDB Entry 50021145: Annual review of PROTAC degraders as anticancer agents in 2022.
BindingDB (2025) · UC San Diego · doi:10.7270/q2805771
BindingDB (2020) · UC San Diego · doi:10.7270/q2dj5j9d
BindingDB (2020) · UC San Diego · doi:10.7270/q2125w6z
BindingDB Entry 50019728: Novel Medicinal Chemistry Strategies Targeting CDK5 for Drug Discovery.
BindingDB (2024) · UC San Diego · doi:10.7270/q2fx7fv6
BindingDB (2022) · UC San Diego · doi:10.7270/q2348q6b
BindingDB (2020) · UC San Diego · doi:10.7270/q2pg1v9d
BindingDB Entry 50017151: Lessons Learned from Past Cyclin-Dependent Kinase Drug Discovery Efforts.
BindingDB (2023) · UC San Diego · doi:10.7270/q2bv7mpd
BindingDB (2022) · UC San Diego · doi:10.7270/q2fb56k3
BindingDB (2022) · UC San Diego · doi:10.7270/q2ks6w6j
BindingDB Entry 50018115: CDK9 inhibitors in cancer research.
BindingDB (2024) · UC San Diego · doi:10.7270/q24b35h7
BindingDB (2021) · UC San Diego · doi:10.7270/q23f4t3t
BindingDB (2021) · UC San Diego · doi:10.7270/q20p13kr
BindingDB Entry 50019988: Development of potent and selective degraders of PI5P4Kγ.
BindingDB (2024) · UC San Diego · doi:10.7270/q2mk6j8j
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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