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. BrownCyril H. Benes, Jarrod A. Marto, Richard A. Young, Nathanael S. Gray

Research output: Contribution to journalArticlepeer-review

666 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

Bibliographical note

Funding Information:
Acknowledgements We thank members of theGray and Young laboratories for helpful discussions; D. Orlando, L. Lawton and L. Anders for advice; and C. Thoreen and D. Sabatini, as well as S. Cheng and G. Morin, for reagents. We thank K. Jones and N. Kohl for performing mouse studies and K. Jones and C. Christensen for prepping mouse tissues. We thank S. Riddle for performing LanthaScreen Eu Kinase Assays. This work was supported by the National Institutes of Health (R01 CA130876-04 and U54 HG006097-02 to N.S.G.; CA178860-01 and P01 NS047572-10 to J.A.M.; HG002668 and CA109901 to R.A.Y.), and the American Cancer Society Postdoctoral Fellowship 120272-PF-11-042-01-DMC (P.B.R.). J.R.B. is a Scholar in Clinical Research of the LeukemiaLymphoma Society andissupported bythe TranslationalResearchProgram of the Leukemia Lymphoma Society and by the American Cancer Society.

ASJC Scopus subject areas

  • General

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