RT Journal Article
SR Electronic
T1 A Chemical Toolbox for the Study of Bromodomains and Epigenetic Signaling
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 391870
DO 10.1101/391870
A1 Qin Wu
A1 David Heidenreich
A1 Stanley Zhou
A1 Suzanne Ackloo
A1 Genevieve Deblois
A1 Shili Duan
A1 Kiran Nakka
A1 Jeffrey Dilworth
A1 Mathieu Lupien
A1 Paul E. Brennan
A1 Cheryl H. Arrowsmith
A1 Susanne Müller
A1 Oleg Fedorov
A1 Panagis Filippakopoulos
A1 Stefan Knapp
YR 2018
UL http://biorxiv.org/content/early/2018/08/14/391870.abstract
AB 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.