The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Targeting transcription regulation in cancer with a covalent CDK7 inhibitor
Open accessAbstract
Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.
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Cites
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Metadata
- Authors
- Kwiatkowski, N., Zhang, T., Rahl, P. B., Abraham, B. J., Reddy, J., Ficarro, S. B., Dastur, A., Amzallag, A., Ramaswamy, S., Tesar, B., Jenkins, C. E., Hannett, N. M., McMillin, D., Sanda, T., Sim, T., Kim, N. D., Look, T., Mitsiades, C. S., Weng, A. P., Brown, J. R., Benes, C. H., Marto, J. A., Young, R. A., & Gray, N. S.
- Venue
- Nature
- Published
- 2014-06-22
- Volume
- 511
- Issue
- 7511
- Pages
- 616-620
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2171613528
- Cited by
- 855
- References
- 30
- FWCI
- 19.96
- Type
- journal article
- Language
- en
- Open access
- green
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- Kwiatkowski, N., Zhang, T., Rahl, P. B., Abraham, B. J., Reddy, J., Ficarro, S. B., Dastur, A., Amzallag, A., Ramaswamy, S., Tesar, B., Jenkins, C. E., Hannett, N. M., McMillin, D., Sanda, T., Sim, T., Kim, N. D., Look, T., Mitsiades, C. S., Weng, A. P., . . . Gray, N. S. (2014). Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature. https://doi.org/10.1038/nature13393
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
