Chemical probes for histone-modifying enzymes

Abstract

The histone-modifying enzymes that catalyze reversible lysine acetylation and methylation are central to the epigenetic regulation of chromatin remodeling. From the early discovery of histone deacetylase inhibitors to the more recent identification of histone demethylase blockers, chemical approaches offer increasingly sophisticated tools for the investigation of the structure and function of these lysine-modifying enzymes. This review summarizes progress to date on compounds identified from screens or by design that can modulate the activity of classical histone deacetylases, sirtuins, histone acetyltransferases, histone methyltransferases and histone demethylases. We highlight applications of compounds to mechanistic and functional studies involving these enzymes and discuss future challenges regarding target specificity and general utility.

Figure 1

Reversible histone acetylation catalyzed by histone acetyltransferases (HATs), classical histone deacetylases (HDACs), and sirtuins (Sir2s). Transferred acetyl group is highlighted in blue. R = 3',5'-adenosine diphosphate; R₁ = adenosine 5'-diphosphate.

Figure 2

Reversible histone methylation catalyzed by histone methyltransferases, LSD1 demethylase, and Jmj demethylases. Transferred methyl group highlighted in red. R = methyl or hydrogen; R₁ = ribose-adenosine 5'-diphosphosphate.

Figure 3

Selected classical histone deacetylase inhibitors. Warhead features highlighted in red.

Figure 4

Activators and inhibitors of Sir2 enzymes.

Figure 5

Natural product and synthetic histone acetyltransferase inhibitors.

Fig. 6

Histone methyltransferase inhibitors.

Figure 7

Histone demethylase inhibitors.