A 6-alkylsalicylate histone acetyltransferase inhibitor inhibits histone acetylation and pro-inflammatory gene expression in murine precision-cut lung slices.
Lysine acetylations are post-translational modifications of cellular proteins, that are crucial in the regulation of many cellular processes. Lysine acetylations on histone proteins are part of the epigenetic code regulating gene expression and are installed by histone acetyltransferases. Observations that inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease, are characterized by increased histone acetyltransferase activity indicate that development of small molecule inhibitors for these enzymes might be a valuable approach towards new therapies for these diseases. The 6-alkylsalicylate MG149 is a candidate to explore this hypothesis because it has been demonstrated to inhibit the MYST type histone acetyltransferases. In this study, we determined the Kivalue for inhibition of the MYST type histone acetyltransferase KAT8 by MG149 to be 39 ± 7.7 μM. Upon investigating whether the inhibition of histone acetyltransferases by MG149 correlates with inhibition of histone acetylation in murine precision-cut lung slices, inhibition of acetylation was observed using an LC-MS/MS based assay on histone H4 res 4-17, which contains the target lysine of KAT8. Following up on this, upon treatment with MG149, reduced pro-inflammatory gene expression was observed in lipopolysaccharide and interferon gamma stimulated murine precision-cut lung slices. Based on this, we propose that 6-alkylsalicylates such as MG149 have potential for development towards applications in the treatment of inflammatory lung diseases.
Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, The Netherlands.
Thea
T
van den Bosch
Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, The Netherlands.
Niek G J
NGJ
Leus
Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, The Netherlands.
Hannah
H
Wapenaar
Analytical Biochemistry, Groningen Research Institute of Pharmacy, University of Groningen, The Netherlands.
Alexander
A
Boichenko
Analytical Biochemistry, Groningen Research Institute of Pharmacy, University of Groningen, The Netherlands.
Jos
J
Hermans
Analytical Biochemistry, Groningen Research Institute of Pharmacy, University of Groningen, The Netherlands.
Rainer
R
Bischoff
Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, The Netherlands.
Hidde J
HJ
Haisma
Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, The Netherlands. Electronic address: f.j.dekker@rug.nl.
Frank J
FJ
Dekker
D000818:Animals; D002853:Chromatography, Liquid; D005786:Gene Expression Regulation / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D012459:Salicylates / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D001632:Bibenzyls
D051548:Histone Acetyltransferases; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D012459:Salicylates; C000626478:2-(2-(4-heptylphenyl)ethyl)-6-hydroxy-benzoic acid; D001632:Bibenzyls
6-Alkylsalicylate; Acetylation; Acetyltransferase inhibitor; Inflammation; Lung; MG149; MG149 (PubChem CID: 49864204); SAHA (PubChem CID: 5311)