Selective inhibition of BET bromodomains (original) (raw)

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Protein Data Bank

Data deposits

Atomic coordinates and structure factors for the reported crystal structures have been deposited with the Protein Data Bank under accession codes 2OSS, 3MXF and 3ONI.

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Acknowledgements

We are grateful to U. Oppermann, S. Müller, S. Sallan, C. Lathan, P. Rahl, R. Young, K. Lee and K. Shaw for discussions and sharing unpublished information; K. Agu, S. Johnston and L. Li for analytical chemistry support; J. Daley for flow cytometry support; T. Bowman, T. Caron, C. Marvin and S. Rodig for immunohistochemistry; and A. Bass for sharing cell lines. The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., Inc., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research and the Wellcome Trust. This research was supported by a Graduate Fellowship from the Chemistry-Biochemistry-Biology Interface Program at the University of Notre Dame, NIGMS T32-075762 (to Y.S.), the DF/HCC (to C.A.F. and J.E.B.), the National Institutes of Health, the Burroughs Wellcome Fund, and the Leukemia & Lymphoma Society (to J.E.B.).

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Author notes

1. Panagis Filippakopoulos, Jun Qi and Sarah Picaud: These authors contributed equally to this work.

Authors and Affiliations

1. Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK,
   Panagis Filippakopoulos, Sarah Picaud, Oleg Fedorov, Tracey Keates, Ildiko Felletar, Martin Philpott, Tom D. Heightman & Stefan Knapp
2. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA,
   Jun Qi, William B. Smith, Elizabeth M. Morse, Michael R. McKeown, Nathan West & James E. Bradner
3. Walther Cancer Research Center and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, 46556, Indiana, USA
   Yao Shen & Olaf Wiest
4. Department of Pathology, Brigham & Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA,
   Tyler T. Hickman, Michael J. Cameron, Brian Schwartz & Christopher A. French
5. Department of Clinical Pharmacology, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK,
   Shonagh Munro, Nicholas La Thangue & Stefan Knapp
6. Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA,
   Michael R. McKeown & James E. Bradner
7. Department of Imaging, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA,
   Yuchuan Wang
8. Lurie Family Imaging Center, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA,
   Amanda L. Christie & Andrew L. Kung
9. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children’s Hospital, Boston, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA,
   Andrew L. Kung

Authors

1. Panagis Filippakopoulos
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2. Jun Qi
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3. Sarah Picaud
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4. Yao Shen
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5. William B. Smith
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6. Oleg Fedorov
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7. Elizabeth M. Morse
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8. Tracey Keates
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9. Tyler T. Hickman
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10. Ildiko Felletar
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11. Martin Philpott
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12. Shonagh Munro
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13. Michael R. McKeown
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14. Yuchuan Wang
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15. Amanda L. Christie
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16. Nathan West
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17. Michael J. Cameron
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18. Brian Schwartz
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19. Tom D. Heightman
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20. Nicholas La Thangue
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21. Christopher A. French
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22. Olaf Wiest
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23. Andrew L. Kung
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24. Stefan Knapp
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25. James E. Bradner
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Contributions

P.F., J.Q., S.K. and J.E.B. designed the study, analysed data and wrote the manuscript. P.F. and S.P. performed and analysed biophysical studies. J.Q. and J.E.B. designed JQ1 and established the synthetic routes. Y.S. and O.W. completed docking and molecular dynamics studies. O.F. performed and analysed DSF. S.M. and N.L.T. contributed biochemical assays. M.R.M., M.P. and T.D.H. performed and analysed alpha-screen assays. W.B.S., M.J.C. and J.E.B. performed in vitro NMC studies and immunohistochemistry. E.M.M. performed flow cytometry studies. E.M.M. and N.W. performed proliferation studies. T.T.H., M.J.C., C.A.F. and J.E.B. completed FRAP studies. M.R.M. and B.S. performed expression analysis. Y.W., A.L.C. and A.L.K. completed in vivo efficacy studies. T.K. and I.F. expressed and purified proteins. S.K. and J.E.B. supervised the research.

Corresponding authors

Correspondence toStefan Knapp or James E. Bradner.

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The authors declare no competing financial interests.

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Filippakopoulos, P., Qi, J., Picaud, S. et al. Selective inhibition of BET bromodomains.Nature 468, 1067–1073 (2010). https://doi.org/10.1038/nature09504

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• Received: 05 May 2010
• Accepted: 17 September 2010
• Published: 24 September 2010
• Issue Date: 23 December 2010
• DOI: https://doi.org/10.1038/nature09504