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Review
. 2018 Jun 5;373(1748):20170069.
doi: 10.1098/rstb.2017.0069.

Epigenetic drug discovery: a success story for cofactor interference

A Ganesan  1   2
Affiliations
Review

Epigenetic drug discovery: a success story for cofactor interference

A Ganesan. Philos Trans R Soc Lond B Biol Sci. .

Abstract

Within the past two decades, seven epigenetic drugs have received regulatory approval and numerous other candidates are currently in clinical trials. Among the epigenetic targets are the writer and eraser enzymes that are, respectively, responsible for the reversible introduction and removal of structural modifications in the nucleosome. This review discusses the progress achieved in the design and development of inhibitors against the key writer and eraser pairs: DNA methyltransferases and Tet demethylases; lysine/arginine methyltransferases and lysine demethylases; and histone acetyltransferases and histone deacetylases. A common theme for the successful inhibition of these enzymes in a potent and selective manner is the targeting of the cofactors present in the active site, namely zinc and iron cations, S-adenosylmethione, nicotinamide adenine dinucleotide, flavin adenine dinucleotide and acetyl Coenzyme A.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.

Keywords: cofactors; enzyme inhibitors; epigenetics.

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Conflict of interest statement

I have no competing interests.

Figures

Figure 1.
Figure 1.
The histone acetyltransferase (KAT)-catalysed acylation of lysine residues.
Figure 2.
Figure 2.
Lysine deacylation catalysed by zinc-dependent HDACs.
Figure 3.
Figure 3.
Lysine deacylation catalysed by sirtuins (Sirts).
Figure 4.
Figure 4.
Lysine methylation catalysed by lysine methyltransferases (KMTs).
Figure 5.
Figure 5.
Arginine methylation catalysed by protein arginine methyltransferases (PRMTs).
Figure 6.
Figure 6.
Lysine demethylation catalysed by lysine-specific demethylases (LSD, KDM1).
Figure 7.
Figure 7.
Lysine demethylation catalysed by Jumonji C demethylases (JmjC, KDM2–7).
Figure 8.
Figure 8.
Arginine demethylation catalysed by Jumonji C demethylases (JmjC, KDM2–7).
Figure 9.
Figure 9.
Cytosine methylation catalysed by DNA methyltransferases.
Figure 10.
Figure 10.
Cytosine demethylation catalysed by Tet dioxygenases.
Figure 11.
Figure 11.
The five approved HDAC inhibitors, with the common pharmacophore indicated for vorinostat and zinc-binding atoms shown in red.
Figure 12.
Figure 12.
Examples of ‘extreme’ HDAC inhibitors. Azumamide is a macrocyclic natural product, and an analogue without a zinc-binding group still inhibits the enzyme. CUDC-101 is a dual target inhibitor designed by grafting a zinc-binding inhibitor onto the approved drug erlotinib.
Figure 13.
Figure 13.
Examples of iron (II)-binding inhibitors of Jumonji C lysine demethylases.
Figure 14.
Figure 14.
Mechanism of action of the DNA methyltransferase inhibitors azacitidine and decitabine.
Figure 15.
Figure 15.
Examples of SAM competitive DNA methyltransferase inhibitors.
Figure 16.
Figure 16.
Examples of SAM-mimetic reversible inhibitors of lysine methyltransferases.
Figure 17.
Figure 17.
Examples of substrate mimetic inhibitors of protein methyltransferases.
Figure 18.
Figure 18.
Examples of nicotinamide-based inhibitors of sirtuin deacylases.
Figure 19.
Figure 19.
Mechanism of action of phenelzine and tranylcypromine, irreversible MAO/LSD1 inhibitors and structures of second-generation analogues.
Figure 20.
Figure 20.
Structures of p300 histone acetyltransferase inhibitors competitive with acetyl Coenzyme A.
See this image and copyright information in PMC

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