Publication

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

van den Bosch, T., Boichenko, A., Leus, N. G. J., Ourailidou, M. E., Wapenaar, H., Rotili, D., Mai, A., Imhof, A., Bischoff, R., Haisma, H. J. & Dekker, F. J., 15-Feb-2016, In : Biochemical Pharmacology. 102, p. 130-140 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

van den Bosch, T., Boichenko, A., Leus, N. G. J., Ourailidou, M. E., Wapenaar, H., Rotili, D., ... Dekker, F. J. (2016). The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases. Biochemical Pharmacology, 102, 130-140. https://doi.org/10.1016/j.bcp.2015.12.010

Author

van den Bosch, Thea ; Boichenko, Alexander ; Leus, Niek G. J. ; Ourailidou, Maria Eleni ; Wapenaar, Hannah ; Rotili, Dante ; Mai, Antonello ; Imhof, Axel ; Bischoff, Rainer ; Haisma, Hidde J. ; Dekker, Frank J. / The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases. In: Biochemical Pharmacology. 2016 ; Vol. 102. pp. 130-140.

Harvard

van den Bosch, T, Boichenko, A, Leus, NGJ, Ourailidou, ME, Wapenaar, H, Rotili, D, Mai, A, Imhof, A, Bischoff, R, Haisma, HJ & Dekker, FJ 2016, 'The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases', Biochemical Pharmacology, vol. 102, pp. 130-140. https://doi.org/10.1016/j.bcp.2015.12.010

Standard

The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases. / van den Bosch, Thea; Boichenko, Alexander; Leus, Niek G. J.; Ourailidou, Maria Eleni; Wapenaar, Hannah; Rotili, Dante; Mai, Antonello; Imhof, Axel; Bischoff, Rainer; Haisma, Hidde J.; Dekker, Frank J.

In: Biochemical Pharmacology, Vol. 102, 15.02.2016, p. 130-140.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

van den Bosch T, Boichenko A, Leus NGJ, Ourailidou ME, Wapenaar H, Rotili D et al. The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases. Biochemical Pharmacology. 2016 Feb 15;102:130-140. https://doi.org/10.1016/j.bcp.2015.12.010


BibTeX

@article{ee9a4133b2644647850a40fa60324020,
title = "The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases",
abstract = "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, applications of histone acetyltransferase inhibitors to reduce inflammatory responses are interesting. 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 regulate the NF-κB pathway; an important pathway in inflammatory responses, which is regulated by acetylation. Interestingly, 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, here we demonstrate 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.",
author = "{van den Bosch}, Thea and Alexander Boichenko and Leus, {Niek G. J.} and Ourailidou, {Maria Eleni} and Hannah Wapenaar and Dante Rotili and Antonello Mai and Axel Imhof and Rainer Bischoff and Haisma, {Hidde J.} and Dekker, {Frank J.}",
note = "Copyright {\circledC} 2015. Published by Elsevier Inc.",
year = "2016",
month = "2",
day = "15",
doi = "10.1016/j.bcp.2015.12.010",
language = "English",
volume = "102",
pages = "130--140",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "PERGAMON-ELSEVIER SCIENCE LTD",

}

RIS

TY - JOUR

T1 - The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases

AU - van den Bosch, Thea

AU - Boichenko, Alexander

AU - Leus, Niek G. J.

AU - Ourailidou, Maria Eleni

AU - Wapenaar, Hannah

AU - Rotili, Dante

AU - Mai, Antonello

AU - Imhof, Axel

AU - Bischoff, Rainer

AU - Haisma, Hidde J.

AU - Dekker, Frank J.

N1 - Copyright © 2015. Published by Elsevier Inc.

PY - 2016/2/15

Y1 - 2016/2/15

N2 - 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, applications of histone acetyltransferase inhibitors to reduce inflammatory responses are interesting. 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 regulate the NF-κB pathway; an important pathway in inflammatory responses, which is regulated by acetylation. Interestingly, 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, here we demonstrate 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.

AB - 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, applications of histone acetyltransferase inhibitors to reduce inflammatory responses are interesting. 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 regulate the NF-κB pathway; an important pathway in inflammatory responses, which is regulated by acetylation. Interestingly, 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, here we demonstrate 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.

U2 - 10.1016/j.bcp.2015.12.010

DO - 10.1016/j.bcp.2015.12.010

M3 - Article

VL - 102

SP - 130

EP - 140

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

ER -

ID: 27260834