Chemical epigenetics to assess the role of HDAC1–3 inhibition in macrophage pro-inflammatory gene expression

Alessia Lenoci,Antonello Mai,Niek G J Leus,Kim Krist,Maria E Ourailidou,Frank J Dekker

doi:10.1039/c6md00375c

Abstract

Azobenzene ortho-aminoanilides inhibit HDACs 1–3 and possess anti-inflammatory properties in murine macrophages.

Highlights

There is a tremendously increasing interest in the development of Histone deacetylases (HDACs) inhibitors (HDACi) as potential therapeutic agents for several pathological conditions
We developed three structural analogues of the clinically-used ortho-aminoanilide type HDAC1–3 inhibitor Entinostat in an attempt to explore the role of class I HDACs in macrophage pro-inflammatory signaling
Studies on the effect of the inhibitors on LPS/IFNγ-induced inflammatory responses in RAW264.7 macrophages revealed that compounds 4 and 9 impaired NF-κB p65 transcriptional activity and suppressed NF-κB p65 nuclear translocation, while an increase was observed in case of compound 7

Summary

Introduction

There is a tremendously increasing interest in the development of HDAC inhibitors (HDACi) as potential therapeutic agents for several pathological conditions. This approach aims at the fine-tuning of the selectivity of inhibitors over specific family members with respect to their pharmacological effects.[34] we set out to design closely related analogues of Entinostat (MS275), an ortho-aminoanilide containing HDAC1–3 inhibitor with proven therapeutic properties, currently undergoing clinical trials for treatment of various cancers.[35] These analogues embody isomeric ortho-aminoanilide-type HDAC inhibitors with an azobenzene cap.

Results

Conclusion