Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Amino Acid Sequence
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Epigenesis, Genetic
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Epithelial Cells / drug effects*
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Gene Expression Regulation, Neoplastic*
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Glucose / deficiency
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Glucose Transporter Type 1 / antagonists & inhibitors
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Glucose Transporter Type 1 / genetics
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Glucose Transporter Type 1 / metabolism
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Glycolysis / drug effects
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Glycolysis / genetics
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High-Throughput Screening Assays
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Histone Acetyltransferases
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Histone Chaperones
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Histones / genetics
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Histones / metabolism
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Humans
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Mammary Glands, Human / metabolism
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Mammary Glands, Human / pathology
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Protein Processing, Post-Translational / drug effects*
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Signal Transduction
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Glucose Transporter Type 1
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Histone Chaperones
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Histones
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Nuclear Proteins
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SLC2A1 protein, human
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Small Molecule Libraries
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BRD1 protein, human
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Histone Acetyltransferases
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Glucose