Journal Article

A chemical toolbox for the study of bromodomains and epigenetic signaling

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

2019

Overview

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 BROMO scan 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. Bromodomains are conserved protein interaction modules that recognize acetyl-lysine modifications. Here the authors present a set of 25 selective small molecule inhibitors covering 29 human bromodomain targets and comprehensively evaluate the selectivity of this probe-set.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/89 / 49 / 49/98 / 631/154 / 631/67 / 631/80 / 631/92 / 96 / Acetylation / Amino Acid Sequence / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / Breast cancer / Cell Line, Tumor / Consortia / Crosstalk / Deprivation / DNA methylation / Epigenesis, Genetic / Epigenetics / Epithelial Cells - drug effects / Epithelial Cells - metabolism / Epithelial Cells - pathology / Gene expression / Gene Expression Regulation, Neoplastic / Genomics / Glucose - deficiency / Glucose Transporter Type 1 - antagonists & inhibitors / Glucose Transporter Type 1 - genetics / Glucose Transporter Type 1 - metabolism / Glycolysis / Glycolysis - drug effects / Glycolysis - genetics / High-Throughput Screening Assays / Histone Acetyltransferases / Histone Chaperones / Histones - genetics / Histones - metabolism / Humanities and Social Sciences / Humans / Inhibitors / Kinases / Lysine / Mammary Glands, Human - metabolism / Mammary Glands, Human - pathology / Modules / multidisciplinary / Nuclear Proteins - antagonists & inhibitors / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Protein Processing, Post-Translational - drug effects / Proteins / Roles / Science / Science (multidisciplinary) / Selectivity / Signal Transduction / Small Molecule Libraries - chemistry / Small Molecule Libraries - pharmacology / Structure-Activity Relationship / Tumor cell lines