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Nat Commun. 2019 Apr 23;10(1):1915. doi: 10.1038/s41467-019-09672-2.

A chemical toolbox for the study of bromodomains and epigenetic signaling.

Author information

1
Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
2
Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 2M9, ON, Canada.
3
Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada.
4
Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, 60438, Frankfurt, Germany.
5
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438, Frankfurt, Germany.
6
Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, ON, Canada.
7
Target Discovery Institute and Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK.
8
Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada. carrow@uhnresearch.ca.
9
Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 2M9, ON, Canada. carrow@uhnresearch.ca.
10
Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada. carrow@uhnresearch.ca.
11
Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, 60438, Frankfurt, Germany. knapp@pharmchem.uni-frankfurt.de.
12
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438, Frankfurt, Germany. knapp@pharmchem.uni-frankfurt.de.
13
German Cancer Network (DKTK), Frankfurt/Mainz, 60438, Frankfurt, Germany. knapp@pharmchem.uni-frankfurt.de.

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.

PMID:
31015424
PMCID:
PMC6478789
DOI:
10.1038/s41467-019-09672-2
[Indexed for MEDLINE]
Free PMC Article

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