Targeting transcription regulation in cancer with a covalent CDK7 inhibitor
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Young_Targeting transcription.pdf
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Author(s)
Kwiatkowski, Nicholas P.
Zhang, Tinghu
Rahl, Peter B.
Abraham, Brian J.
Reddy, Jessica
Ficarro, Scott B.
Dastur, Anahita
Amzallag, Arnaud
Ramaswamy, Sridhar
Tesar, Bethany
Date Issued
June 2014
Journal
Nature
Publisher
Nature Publishing Group
Citation
Kwiatkowski, Nicholas, Tinghu Zhang, Peter B. Rahl, Brian J. Abraham, Jessica Reddy, Scott B. Ficarro, Anahita Dastur, et al. “Targeting Transcription Regulation in Cancer with a Covalent CDK7 Inhibitor.” Nature 511, no. 7511 (June 22, 2014): 616–620.
Version
Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
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DOI of Published Version
https://doi.org/10.1038/nature13393
