Journal Article

Suppression of inflammation by a synthetic histone mimic

Wilson, Paul, Lee, Kevin, Schaefer, Uwe, Kirilovsky, Jorge, Tarakhovsky, Alexander, Dewell, Scott, Prinjha, Rab K., White, Julia, Marazzi, Ivan, Coste, Hervé, Rice, Charles M., Jeffrey, Kate L., Chung, Chun-wa, Beinke, Soren, Nicodeme, Edwige, Chandwani, Rohit, Lora, Jose M.

2010

Overview

Histone mimics target BET bromodomains Small molecules that perturb chromatin proteins are an emerging focus of current biomedical research. Two groups reporting in this issue have targeted bromodomain-containing BET proteins that bind acetylated lysine residues during gene activation, arriving at cell-permeable small molecule compounds with similar structures based on fused triazole-diazepine rings. James Bradner and colleagues report the development of a compound named JQ1. The BET protein BRD4, with two bromodomains, is implicated in human squamous cell carcinoma. JQ1 inhibits the growth of BRD4-dependent tumours in mouse models. Alexander Tarakhovsky and colleagues' inhibitor, I-BET, is shown to interfere with the binding of certain BET family members to acetylated histones. It inhibits activation of pro-inflammatory genes in macrophages and has immunomodulatory activity in a mouse model of inflammatory disease. Post-translationally modified histones are recognized by effector proteins which contain specific binding modules; for example, the bromodomain-containing BET proteins bind acetylated lysine residues during gene activation. Here a synthetic small molecule is described that interferes with the binding of certain BET family members to acetylated histones. The compound inhibits activation of pro-inflammatory genes in macrophages and has activity in a mouse model of inflammatory disease. Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression 1 , 2 , 3 , 4 . Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression 5 , 6 , 7 , 8 , 9 , 10 . Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomain and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by ‘mimicking’ acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154 / 631/250/256/1980 / 631/61/2049 / 631/80 / Acetylation - drug effects / Animals / Anti-Inflammatory Agents - chemistry / Anti-Inflammatory Agents - pharmacology / Anti-Inflammatory Agents - therapeutic use / Benzodiazepines / Cells, Cultured / Chromatin / Epigenomics / Eukaryotes / Gene expression / Gene Expression Regulation - drug effects / Genome-Wide Association Study / Heterocyclic Compounds, 4 or More Rings - chemistry / Heterocyclic Compounds, 4 or More Rings - pharmacology / Heterocyclic Compounds, 4 or More Rings - therapeutic use / Histone Deacetylase Inhibitors - pharmacology / Humanities and Social Sciences / Hydroxamic Acids - pharmacology / Immune system / Immunology / Inflammation - drug therapy / Inflammation - prevention & control / Kaplan-Meier Estimate / letter / Lipopolysaccharides - pharmacology / Macrophages - drug effects / Mice / Mice, Inbred C57BL / Models, Molecular / multidisciplinary / Pathology / Pharmacology / Protein Structure, Tertiary / Protein-Serine-Threonine Kinases - metabolism / Proteins / Salmonella Infections - drug therapy / Salmonella Infections - immunology / Salmonella Infections - physiopathology / Salmonella Infections - prevention & control / Salmonella typhimurium / Science / Science (multidisciplinary) / Sepsis - drug therapy / Sepsis - prevention & control / Shock, Septic - drug therapy / Shock, Septic - prevention & control