The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases

Thea van den Bosch, Alexander Boichenko, Niek G J Leus, Maria E Ourailidou, Hannah Wapenaar, Dante Rotili, Antonello Mai, Axel Imhof, Rainer Bischoff, Hidde J Haisma, Frank J Dekker

Research output: Contribution to journalArticlepeer-review


Lysine acetylations are reversible posttranslational modifications of histone and non-histone proteins that play important regulatory roles in signal transduction cascades and gene expression. Lysine acetylations are regulated by histone acetyltransferases as writers and histone deacetylases as erasers. Because of their role in signal transduction cascades, these enzymes are important players in inflammation. Therefore, histone acetyltransferase inhibitors could reduce inflammatory responses. Among the few histone acetyltransferase inhibitors described, C646 is one of the most potent (Ki of 0.4μM for histone acetyltransferase p300). C646 was described to affect the NF-κB pathway; an important pathway in inflammatory responses, which is regulated by acetylation. This pathway has been implicated in asthma and COPD. Therefore, we hypothesized that via regulation of the NF-κB signaling pathway, C646 can inhibit pro-inflammatory gene expression, and have potential for the treatment of inflammatory lung diseases. In line with this, we demonstrate here that C646 reduces pro-inflammatory gene expression in RAW264.7 murine macrophages and murine precision-cut lung slices. To unravel its effects on cellular substrates we applied mass spectrometry and found, counterintuitively, a slight increase in acetylation of histone H3. Based on this finding, and structural features of C646, we presumed inhibitory activity of C646 on histone deacetylases, and indeed found inhibition of histone deacetylases from 7μM and higher concentrations. This indicates that C646 has potential for further development towards applications in the treatment of inflammation, however, its newly discovered lack of selectivity at higher concentrations needs to be taken into account.

Original languageEnglish
Pages (from-to)130-140
Number of pages11
JournalBiochemical Pharmacology
Publication statusPublished - 15 Feb 2016


  • amino acid sequence
  • animals
  • benzoates
  • cell line
  • dose-response relationship
  • gene expression regulation
  • histone deacetylase inhibitors
  • histone deacetylases
  • inflammation Mediators/antagonists & inhibitors
  • lung
  • mice
  • molecular sequence data
  • NF-kappa B
  • organ culture techniques
  • pyrazoles
  • p300-CBP transcription factors
  • pharmacology
  • drug effects
  • antagonists & inhibitors
  • genetics


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