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Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors
Open accessAbstract
Cyclin-dependent kinases 12 and 13 (CDK12 and 13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and 13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and 13 covalent inhibitor, THZ531. Co-crystallization with CDK12-cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super–enhancer–associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and 13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.
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“THZ53124, a bulky covalent CDK12/13 inhibitor predicted to clash with DDB1 (Extended Data Fig. 6d–f), locks the CDK12 C-terminal extension in a conformation incompatible with DDB1 recruitment (Extended Data Fig. 6d).”
From The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K (2020) · cites this paper as [24]
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“Consistent with this notion, HQ461-mediated depletion of Cyclin K phenotypically mimics dual inhibition of CDK12 and CDK13 by the CDK12/13-selective inhibitor THZ531 to trigger cell death (Zhang et al., 2016).”
From Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation (2020) · cites this paper as Zhang et al., 2016
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“Consistently, THZ531 further decreased the TR-FRET signal and diminished cycK ubiquitination in vitro below DMSO control levels (Fig. 3d, Extended Data Fig. 6c, f)24.”
From The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K (2020) · cites this paper as [24]
Experimental — accuracy not yet measuredIn the citing paper
“THZ531, a CDK12-CDK13 covalent inhibitor, binds with CDK12-cyclin K via a cysteine residue that is located outside the kinase domain [97].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [97]
In the citing paper
“Furthermore, THZ531 induced cell death and apoptosis in Ewing sarcoma cancer cell lines.”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [97]
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Metadata
- Authors
- Zhang, T., Kwiatkowski, N., Olson, C. M., Dixon-Clarke, S. E., Abraham, B. J., Greifenberg, A. K., Ficarro, S. B., Elkins, J. M., Liang, Y., Hannett, N. M., Manz, T., Hao, M., Bartkowiak, B., Greenleaf, A. L., Marto, J. A., Geyer, M., Bullock, A. N., Young, R. A., & Gray, N. S.
- Affiliations
- Harvard University (US)
- University of Oxford (GB)
- Whitehead Institute for Biomedical Research (US)
- University of Bonn (DE)
- Dana-Farber Cancer Institute (US)
- Duke Medical Center (US)
- Corresponding author
- Young, Richard A
- Gray, Nathanael S
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2016-08-29
- Volume
- 12
- Issue
- 10
- Pages
- 876-884
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC5033074
- OpenAlex
- W2512442926
- Semantic Scholar
- c8164ef9df7e4d3d418a7b07384190780d6ae6a3
- Cited by
- 374
- References
- 59
- Citations by year
- 2026: 39 · 2025: 35 · 2024: 50 · 2023: 44 · 2022: 40 · 2021: 49 · 2020: 38 · 2019: 27 · 2018: 21 · 2017: 27 · 2016: 4
- FWCI
- 13.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- PMC
- Funders
- Eli Lilly and Company
- Pfizer
- GlaxoSmithKline
- Dana-Farber/Harvard Cancer Center
- Genome Canada (OGI-055)
- Wellcome Trust (106169/Z/14/Z, 092809, 106169, 092809/Z/10/Z, 1097737)
- Diamond Light Source (mx8421, 1097737)
- Ontario Genomics
- Hope Funds for Cancer Research
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- Ontario Genomics Institute (OGI-055, 092809/Z/10/Z)
- Ontario Ministry of Economic Development and Innovation (092809/Z/10/Z)
- Deutsche Forschungsgemeinschaft (GE 976/9-1)
- Ministero dello Sviluppo Economico
- National Institutes of Health (CA109901, CA179483)
- Medical Research Council
- National Human Genome Research Institute (R01HG002668)
- National Cancer Institute (R01CA179483, P01CA109901, P30CA014051)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Chemistry › Organic Chemistry › Heterocyclic Compound Synthesis and Bioactivity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- CDK12, CDK13, covalent inhibitors, cyclin K, RNA polymerase II processivity, super-enhancers, DNA damage response genes, transcription factor expression, apoptosis, kinase inhibitors
- MeSH terms
- Anilides, Cysteine, DNA Damage, Humans, Pyrimidines, CDC2 Protein Kinase, Cell Death, Cyclin-Dependent Kinases, Protein Kinase Inhibitors
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