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A chemical toolbox for the study of bromodomains and epigenetic signaling

Author

Listed:
  • Qin Wu

    (University of Toronto
    University Health Network
    University of Toronto)

  • David Heidenreich

    (University of Toronto
    Goethe-University Frankfurt)

  • Stanley Zhou

    (University Health Network
    University of Toronto)

  • Suzanne Ackloo

    (University of Toronto)

  • Andreas Krämer

    (Goethe-University Frankfurt
    Goethe-University Frankfurt)

  • Kiran Nakka

    (Ottawa Hospital Research Institute)

  • Evelyne Lima-Fernandes

    (University of Toronto
    University Health Network
    University of Toronto)

  • Genevieve Deblois

    (University Health Network
    University of Toronto)

  • Shili Duan

    (University Health Network
    University of Toronto)

  • Ravi N. Vellanki

    (University Health Network)

  • Fengling Li

    (University of Toronto)

  • Masoud Vedadi

    (University of Toronto)

  • Jeffrey Dilworth

    (Ottawa Hospital Research Institute)

  • Mathieu Lupien

    (University Health Network
    University of Toronto)

  • Paul E. Brennan

    (University of Oxford)

  • Cheryl H. Arrowsmith

    (University of Toronto
    University Health Network
    University of Toronto)

  • Susanne Müller

    (Goethe-University Frankfurt
    Goethe-University Frankfurt)

  • Oleg Fedorov

    (University of Oxford)

  • Panagis Filippakopoulos

    (University of Oxford)

  • Stefan Knapp

    (Goethe-University Frankfurt
    Goethe-University Frankfurt
    Frankfurt/Mainz)

Abstract

Bromodomains (BRDs) are conserved protein interaction modules which recognize (read) acetyl-lysine modifications, however their role(s) in regulating cellular states and their potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set of 25 chemical probes, selective small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate the selectivity of this probe-set using BROMOscan and demonstrate the utility of the set identifying roles of BRDs in cellular processes and potential translational applications. For instance, we discovered crosstalk between histone acetylation and the glycolytic pathway resulting in a vulnerability of breast cancer cell lines under conditions of glucose deprivation or GLUT1 inhibition to inhibition of BRPF2/3 BRDs. This chemical probe-set will serve as a resource for future applications in the discovery of new physiological roles of bromodomain proteins in normal and disease states, and as a toolset for bromodomain target validation.

Suggested Citation

  • Qin Wu & David Heidenreich & Stanley Zhou & Suzanne Ackloo & Andreas Krämer & Kiran Nakka & Evelyne Lima-Fernandes & Genevieve Deblois & Shili Duan & Ravi N. Vellanki & Fengling Li & Masoud Vedadi & J, 2019. "A chemical toolbox for the study of bromodomains and epigenetic signaling," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09672-2
    DOI: 10.1038/s41467-019-09672-2
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    Cited by:

    1. Nathaniel G. Jones & Vincent Geoghegan & Gareth Moore & Juliana B. T. Carnielli & Katherine Newling & Félix Calderón & Raquel Gabarró & Julio Martín & Rab K. Prinjha & Inmaculada Rioja & Anthony J. Wi, 2022. "Bromodomain factor 5 is an essential regulator of transcription in Leishmania," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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