A chemical toolbox for the study of bromodomains and epigenetic signaling

  • 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.
Author:Qin Wu, David 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
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/31015424
Parent Title (English):Nature Communications
Publisher:Nature Publishing Group UK
Place of publication:[London]
Document Type:Article
Year of Completion:2019
Date of first Publication:2019/04/23
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/04/29
Tag:Cancer; Cell biology; Chemical biology; Drug discovery
Issue:1, Art. 1915
Page Number:14
First Page:1
Last Page:14
Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Exzellenzcluster / Exzellenzcluster Makromolekulare Komplexe
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0