2010
DOI: 10.1038/nature09589
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Suppression of inflammation by a synthetic histone mimic

Abstract: Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, while 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 expression1–4. Recognition of post-translationally mod… Show more

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Cited by 1,416 publications
(1,769 citation statements)
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References 27 publications
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“…In LPS-activated macrophages, BET inhibition reduced the levels of H3ac, H4K5ac, H4K8ac, H4K12ac, and total H4ac on promoters of the induced genes [38]. This reduction is presumably due to increased accessibility of HDAC to the exposed BET protein binding sites by preventing the formation of multi-molecular complexes containing histone acetyltransferases (HATs) and other transcription machineries [38], as shown by the reduced level of positive transcription elongation factor b (P-TEFb/CDK9) and RNA polymerase II on the affected regions [38]. In H23 cells, however, a subset of BRD2-bound genes involved in RNA processing, such as POL2RA and CDK9, was in fact upregulated, and the transcription levels of HATs, such as KAT2A and EP300, were not affected by JQ1.…”
Section: Discussionmentioning
confidence: 99%
“…In LPS-activated macrophages, BET inhibition reduced the levels of H3ac, H4K5ac, H4K8ac, H4K12ac, and total H4ac on promoters of the induced genes [38]. This reduction is presumably due to increased accessibility of HDAC to the exposed BET protein binding sites by preventing the formation of multi-molecular complexes containing histone acetyltransferases (HATs) and other transcription machineries [38], as shown by the reduced level of positive transcription elongation factor b (P-TEFb/CDK9) and RNA polymerase II on the affected regions [38]. In H23 cells, however, a subset of BRD2-bound genes involved in RNA processing, such as POL2RA and CDK9, was in fact upregulated, and the transcription levels of HATs, such as KAT2A and EP300, were not affected by JQ1.…”
Section: Discussionmentioning
confidence: 99%
“…Additionally, JQ1 was shown to have therapeutic effects in multiple myelomas, through regulation of the Myc oncogenic driver in these tumors [100]. Another benzodiazepine scaffold (IBET) was shown to exhibit great potential as an anti-inflammatory agent, by reducing expression of pro-inflammatory genes in activated macrophages [20].…”
Section: Inhibition Of Brd-specific K Ac Readoutmentioning
confidence: 99%
“…CPI-3) 13 and with what others have observed with related scaffolds. 4,5 Substitutions at other positions of the benzo ring or at the 1 position of the isoxazole diminished potency (data not shown).…”
mentioning
confidence: 91%
“…Specifically, we hypothesized that changing the cyclic imine to a substituted aniline would retain the concave shape important for specific binding to the bromodomain while providing a different metabolic profile for the series. We were also interested in evaluating a modified linker in combination with the reported triazole binding element 4,5 and in finding a replacement for the thiophene group of CPI-3 because of its potential metabolic instability. Here we describe the resulting benzo [b]isoxazolo- [4,5-d]azepine and benzotriazolo [4,3-d] [1,4]diazepine series, which were potent inhibitors of BET bromodomains in biochemical and cellular assays and which allowed for optimization of metabolic stability and demonstration of a pharmacodynamic effect in a mouse model of IL-6 suppression (Scheme 1).…”
mentioning
confidence: 99%