Small Molecule Inhibitors of Histone Acetyltransferases as Epigenetic Tools and Drug Candidates

Abstract

Alteration of the acetylation state of histone proteins contributes to transcriptional regulation and epigenetic inheritance. Dysregulation of these processes may lead to human diseases, especially cancer. One of the major chromatin modifications is histone acetylation and this review gives an overview of the role of histone acetyltransferases, their structural aspects, as well as of chemical modulators targeting their enzymatical activities. Inhibitors and activators of histone acetyltransferases are presented and their capability to influence histone and non-histone protein acetylation levels is discussed. Development of small molecules as epigenetic tools that alter histone acetyltransferase activity will be helpful to better understand the consequences of histone and generally protein acetylation and potentially offer novel therapeutic approaches for the treatment of cancer and other diseases.

Structural basis for acyl group discrimination by human Gcn5L2

“…Interestingly, a recent study profiling the acyl chain specificity of Gcn5 observed potent inhibition by long fatty acyl-CoA molecules like palmitoyl-CoA (Montgomery et al), further supporting the idea that acyl-CoA molecules may function as natural KAT inhibitors. Although relatively few synthetic inhibitors for KATs have been developed, some of the most potent compounds exploit CoA-based scaffolds with structural complementarity to the active site (Furdas et al, 2012). Bisubstrate analogues comprised of CoA-peptide conjugates mimic the ternary complex and inhibit Gcn5 at micromolar concentrations (Poux et al, 2002).…”

GCN5 Protects Vertebrate Cells against UV-irradiation via Controlling Gene Expression of DNA Polymerase η

“…SHM introduces nucleotide substitution into immunoglobulin variable genes to increase antibody diversity. In the recent 10 years, HATs and histone deacetylases have become subjects of interest as targets of drug innovation (38,39). Expression of tens of thousands of genes should be regulated by HATs, though less than 20 HATs have been found in vertebrates (28).…”

Analysis of the mechanism by which dADA2 factors contribute to the specificity of dSAGA and dATAC histone acetyltransferase complexes

“…The amino terminal tail of histones has over 60 residues which have been shown to undergo enzymatic modifications in different cell types and during developmental stages (Surani et al, 2007;Furdas et al, 2012). At least seven covalent modifications are known to date: acetylation (at lysine residues), methylation (lysine and arginine), phosphorylation (serine and threonine), ubiquitination (lysine), sumoylation (lysine), ADP ribosylation (glutamate and lysine), deamination (arginine) as well as proline isomerization ( Fig.…”

“…Considering its involvement in essential cellular processes such as gene expression, vascular remodelling, cell differentiation, neuronal plasticity, inflammation or metabolic events, lysine acetylation can be regarded as a master regulator in cellular biology (Furdas et al, 2012).…”

“… MYST family, including the founding members MOZ, Ybf2/Sas3, Sas2 and Tip60 that are involved in the regulation of a variety of DNA-mediated reactions (Fukuda et al, 2006);  CBP/p300 family named after the two human paralogs p300 and CBP with a wide substrate specificity for histones and role in gene transcription regulation Ogryzko et al, 1996);  Transcriptional Factors-related HATs family (Mizzen et al, 1996);  Nuclear Receptor coactivator families (Hodawadekar and Marmorstein, 2007;Furdas et al, 2012).…”