Suppression of inflammation by a synthetic histone mimic

By E. Nicodeme, K. Jeffrey, Uwe Schaefer, S. Beinke, Scott B. Dewell, C. Chung, R. Chandwani, Ivan Marazzi, Paul A. Wilson, H. Coste and 6 more. Nature, 2010

1,510 citations recorded by the source corpus.

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. 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. 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/54091d767213300fa3ad9c5cf6ba2c5876e2eeac

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Citations in the corpus

Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “JQ-1 and I-BET are the first two compounds that can inhibit bromodomain-containing BET (bromodomain and extraterminal) proteins by binding to the bromodomain of the BET proteins (Filippakopoulos et al., 2010; Nicodeme et al., 2010; Zuber et al., 2011).”
Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers (2013, background): “Two recently developed bromodomain inhibitors, JQ1 and iBET, selectively bind to the amino-terminal twin bromodomains of BRD4 (Filippakopoulos et al., 2010; Nicodeme et al., 2010).”
Transcriptional regulation of macrophage polarization: enabling diversity with identity (2011, background): “Second, these additional layers of regulation provide a potential target for pharmacological intervention, as exemplified by the identification of a small anti-inflammatory molecule, iBET, that has some selectivity for slowly activated, secondary response genes in macrophage”
Cancer epigenetics: from mechanism to therapy. (2012, background): “For example, the BET protein inhibitors alter only a few hundred genes, and these genes differ depending on cell type (Dawson et al., 2011; Nicodeme et al., 2010).”
Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family (2012, background): “It is likely that selective inhibitors capable of targeting BRDs will find broad application in medicine and basic research as exemplified by the recent development of highly specific and potent acetyl-lysine competitive BET BRD inhibitors (Chung et al., 2011; Dawson et al., 2011; Delmore et al., 20”
Targeting MYC dependence in cancer by inhibiting BET bromodomains (2011, background): “Given that HDAC inhibition blocked the transcriptional affects of BET bromodomain inhibition in the context of NF-κB signaling (7), it will be interesting to test the relationship between BET bromodomain inhibition and HDAC inhibition with respect to MYC suppression.”
Cancer Genetics and Epigenetics: Two Sides of the Same Coin? (2012, background): “Selective bromodomain inhibitors (JQ1 or GSK525762) (Filippakopoulos et al., 2010; Nicodeme et al., 2010) inhibit transcription by MYC, which is overexpressed in a majority of cancers (Delmore et al.”
Trained immunity: a program of innate immune memory in health and disease (2016, background): “Moreover, since histone modifications are specifically bound by recognition domains contained in various proteins implicated in transcriptional control (as in the case of the bromodomain-acetyl lysine interaction) (74), the persistence of histone modifications deposited at promoters or enhancers aft”
RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia (2011, background): “The recent development of small-molecule BET bromodomain inhibitor”
BET bromodomain inhibition as a therapeutic strategy to target c-Myc (2011, positive): “This effect was BET bromodomain specific, supported by the nearly comparable activity of an analogous BET inhibitor subsequently published by Glaxo SmithKline (iBET) (Figure 1A) (Nicodeme et al., 2010) and the lack of activity of the inactive (-)- JQ1 enantiomer, which we previously characterized as”