Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

Nicholas Kwiatkowski, Tinghu Zhang, Peter B. Rahl, Brian J. Abraham, Jessica Reddy, Scott B. Ficarro, Anahita Dastur, Arnaud Amzallag, Sridhar Ramaswamy, Bethany Tesar, Catherine E. Jenkins, Nancy M. Hannett, Douglas McMillin, Takaomi Sanda, Taebo Sim, Nam Doo Kim, Thomas Look, Constantine S. Mitsiades, Andrew P. Weng, Jennifer R. Brown & 4 others Cyril H. Benes, Jarrod A. Marto, Richard A. Young, Nathanael S. Gray

Research output: Contribution to journalArticle

260 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)616-620
Number of pages5
JournalNature
Volume511
Issue number7511
DOIs
Publication statusPublished - 2014 Jan 1

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Neoplasms
Transcription Factors
Phosphotransferases
Pharmacology
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Cell Line
Jurkat Cells
Cyclin-Dependent Kinases
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Oncogenes
Cysteine
Maintenance
Genome
T-Lymphocytes
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Kwiatkowski, N., Zhang, T., Rahl, P. B., Abraham, B. J., Reddy, J., Ficarro, S. B., ... Gray, N. S. (2014). Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature, 511(7511), 616-620. https://doi.org/10.1038/nature13393

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. / Kwiatkowski, Nicholas; Zhang, Tinghu; Rahl, Peter B.; Abraham, Brian J.; Reddy, Jessica; Ficarro, Scott B.; Dastur, Anahita; Amzallag, Arnaud; Ramaswamy, Sridhar; Tesar, Bethany; Jenkins, Catherine E.; Hannett, Nancy M.; McMillin, Douglas; Sanda, Takaomi; Sim, Taebo; Kim, Nam Doo; Look, Thomas; Mitsiades, Constantine S.; Weng, Andrew P.; Brown, Jennifer R.; Benes, Cyril H.; Marto, Jarrod A.; Young, Richard A.; Gray, Nathanael S.

In: Nature, Vol. 511, No. 7511, 01.01.2014, p. 616-620.

Research output: Contribution to journalArticle

Kwiatkowski, N, Zhang, T, Rahl, PB, Abraham, BJ, Reddy, J, Ficarro, SB, Dastur, A, Amzallag, A, Ramaswamy, S, Tesar, B, Jenkins, CE, Hannett, NM, McMillin, D, Sanda, T, Sim, T, Kim, ND, Look, T, Mitsiades, CS, Weng, AP, Brown, JR, Benes, CH, Marto, JA, Young, RA & Gray, NS 2014, 'Targeting transcription regulation in cancer with a covalent CDK7 inhibitor', Nature, vol. 511, no. 7511, pp. 616-620. https://doi.org/10.1038/nature13393
Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature. 2014 Jan 1;511(7511):616-620. https://doi.org/10.1038/nature13393
Kwiatkowski, Nicholas ; Zhang, Tinghu ; Rahl, Peter B. ; Abraham, Brian J. ; Reddy, Jessica ; Ficarro, Scott B. ; Dastur, Anahita ; Amzallag, Arnaud ; Ramaswamy, Sridhar ; Tesar, Bethany ; Jenkins, Catherine E. ; Hannett, Nancy M. ; McMillin, Douglas ; Sanda, Takaomi ; Sim, Taebo ; Kim, Nam Doo ; Look, Thomas ; Mitsiades, Constantine S. ; Weng, Andrew P. ; Brown, Jennifer R. ; Benes, Cyril H. ; Marto, Jarrod A. ; Young, Richard A. ; Gray, Nathanael S. / Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. In: Nature. 2014 ; Vol. 511, No. 7511. pp. 616-620.
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