A chemical toolbox for the study of bromodomains and epigenetic signaling

A chemical toolbox for the study of bromodomains and epigenetic signaling. Wu, Q., Heidenreich, D., Zhou, S., Ackloo, S., Krämer, A., Nakka, K., Lima-Fernandes, E., Deblois, G., Duan, S., Vellanki, R., N., Li, F., Vedadi, M., Dilworth, J., Lupien, M., Brennan, P., E., Arrowsmith, C., H., Müller, S., Fedorov, O., Filippakopoulos, P., & Knapp, S. Nature Communications, 10(1):1915, Nature Publishing Group, 12, 2019.

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A chemical toolbox for the study of bromodomains and epigenetic signaling [link]

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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.

@article{
 title = {A chemical toolbox for the study of bromodomains and epigenetic signaling},
 type = {article},
 year = {2019},
 keywords = {Cancer,Cell biology,Chemical biology,Drug discovery},
 pages = {1915},
 volume = {10},
 websites = {http://www.nature.com/articles/s41467-019-09672-2},
 month = {12},
 publisher = {Nature Publishing Group},
 day = {23},
 id = {75a8eb40-2577-3ea7-a93f-f198330c3999},
 created = {2019-05-30T09:03:09.972Z},
 accessed = {2019-05-30},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2019-08-07T17:40:12.490Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 citation_key = {Wu2019},
 private_publication = {false},
 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.},
 bibtype = {article},
 author = {Wu, Qin and Heidenreich, David and Zhou, Stanley and Ackloo, Suzanne and Krämer, Andreas and Nakka, Kiran and Lima-Fernandes, Evelyne and Deblois, Genevieve and Duan, Shili and Vellanki, Ravi N. and Li, Fengling and Vedadi, Masoud and Dilworth, Jeffrey and Lupien, Mathieu and Brennan, Paul E. and Arrowsmith, Cheryl H. and Müller, Susanne and Fedorov, Oleg and Filippakopoulos, Panagis and Knapp, Stefan},
 doi = {10.1038/s41467-019-09672-2},
 journal = {Nature Communications},
 number = {1}
}

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