Abstract

Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state1, but direct pharmacological inhibition of transcription factors has so far proven difficult2. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates3, including cyclin-dependent kinases (CDKs)4. 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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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

Sequencing and expression data have been deposited in the Gene Expression Omnibus under accession number GSE50625.

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Acknowledgements

We thank members of the Gray 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 Leukemia Lymphoma Society and is supported by the Translational Research Program of the Leukemia Lymphoma Society and by the American Cancer Society.

Author information

Author notes

    • Nicholas Kwiatkowski
    •  & Tinghu Zhang

    These authors contributed equally to this work.

Affiliations

  1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA

    • Nicholas Kwiatkowski
    • , Tinghu Zhang
    • , Scott B. Ficarro
    • , Jarrod A. Marto
    •  & Nathanael S. Gray
  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Nicholas Kwiatkowski
    • , Tinghu Zhang
    • , Scott B. Ficarro
    • , Jarrod A. Marto
    •  & Nathanael S. Gray
  3. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA

    • Nicholas Kwiatkowski
    • , Peter B. Rahl
    • , Brian J. Abraham
    • , Jessica Reddy
    • , Nancy M. Hannett
    •  & Richard A. Young
  4. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Jessica Reddy
    •  & Richard A. Young
  5. Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA

    • Scott B. Ficarro
    •  & Jarrod A. Marto
  6. Department of Medicine Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA

    • Anahita Dastur
    • , Arnaud Amzallag
    • , Sridhar Ramaswamy
    •  & Cyril H. Benes
  7. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA

    • Arnaud Amzallag
    •  & Sridhar Ramaswamy
  8. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Bethany Tesar
    • , Douglas McMillin
    • , Constantine S. Mitsiades
    •  & Jennifer R. Brown
  9. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Bethany Tesar
    • , Douglas McMillin
    • , Constantine S. Mitsiades
    •  & Jennifer R. Brown
  10. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada

    • Catherine E. Jenkins
    •  & Andrew P. Weng
  11. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Takaomi Sanda
    •  & Thomas Look
  12. Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore

    • Takaomi Sanda
  13. Chemical Kinomics Research Center, Korea Institute of Science and Technology, 39-1, Hawolgok-dong, Seongbuk-gu, Seoul 136-791, Korea, and KU-KIST Graduate School of Converging Science and Technology, 145, Anam-ro, Seongbuk-gu, Seoul 136-713, Korea

    • Taebo Sim
  14. Daegu-Gyeongbuk Medical Innovation Foundation, 2387 dalgubeol-daero, Suseong-gu, Daegu 706-010, Korea

    • Nam Doo Kim
  15. Division of Hematology/Oncology, Children’s Hospital, Boston, Massachusetts 02115 USA

    • Thomas Look

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Contributions

N.S.G., N.K. and T.Z. conceived the project. N.S.G. and T.Z. conceived and directed the chemical synthesis of THZ1 and its analogues with input from T.Si. T.Z. performed chemical synthesis and small-molecule structure determination. R.A.Y., N.S.G., P.B.R. and N.K. conceived genomics studies. N.K., P.B.R., J.R.B., C.H.B., N.S.G. and R.A.Y. designed biological experimental research with input from J.R., B.J.A., D.M., T.Sa., T.L., A.P.W. and C.S.M. N.K., P.B.R., J.R., A.D., B.T., C.E.J. and N.M.H performed experimental biological research. S.B.F. designed and performed protein mass spectrometry on THZ1/CDK7 adducts with input from J.A.M. S.R. and A.A. performed elastic net regression analysis. N.D.K. performed molecular modelling studies with input from T.Sa. B.J.A. designed and performed genomics data analyses. N.K., N.S.G. and R.A.Y. co-wrote the paper. All authors edited the manuscript.

Competing interests

N.S.G., T.Z. and N.K. are inventors on a patent application covering THZ1, which is licensed to a company co-founded by N.S.G. and R.A.Y.

Corresponding authors

Correspondence to Richard A. Young or Nathanael S. Gray.

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https://doi.org/10.1038/nature13393

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