A Chemical Toolbox for the Study of Bromodomains and Epigenetic Signaling

Qin Wu, David Heidenreich, Stanley Zhou, Suzanne Ackloo Genevieve Deblois, Shili Duan, Kiran Nakka, Jeffrey Dilworth, Mathieu Lupien, Paul E. Brennan, Cheryl H. Arrowsmith, Susanne Müller, Oleg Fedorov, Panagis Filippakopoulos, Stefan Knapp

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Aug 21, 2018
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Received Date: 14th August 2018

Bromodomains (BRDs) are evolutionary conserved epigenetic protein interaction modules which recognize (“read”) acetyl-lysine, 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 tool 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 using studies of muscle cell differentiation and triple negative breast cancer (TNBC). We identified cross talk between histone acetylation and the glycolytic pathway resulting in a vulnerability of TNBC cell lines to inhibition of BRPF2/3 BRDs under conditions of glucose deprivation or GLUT1 inhibition. 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.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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