Open Access

Qin Wu, David Jonas Heidenreich, Stanley Zhou, Suzanne Ackloo, Andreas Krämer, Kiran Nakka, Evelyne Lima-Fernandes, Genevieve Deblois, Shili Duan, Ravi N. Vellanki, Fengling Li, Masoud Vedadi, Jeffrey Dilworth, Mathieu Lupien, Paul E. Brennan, Cheryl H. Arrowsmith, Susanne Müller, Oleg Fedorov, Panagis Filippakopoulos, Stefan Knapp

• 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.