The role of histone demethylases in cancer therapy

Abstract

Reversible histone methylation has emerged in the last few years as an important mechanism of epigenetic regulation. Histone methyltransferases and demethylases have been identified as contributing factors in the development of several diseases, especially cancer. Therefore, they have been postulated to be new drug targets with high therapeutic potential. Here, we review histone demethylases with a special focus on their potential role in oncology drug discovery. We present an overview over the different classes of enzymes, their biochemistry, selected data on their role in physiology and already available inhibitors.

Figure 1

Mechanism of demethylation by LSD1. Details can be found in the text.

Figure 2

Mechanism of oxidative demethylation by JMJD. Details can be found in the text.

Figure 3

Covalent LSD1 inhibitors Tranylcypromine (1, PCPA), Pargyline (2), Phenelzine (3) and various PCPA analogs.

Figure 4

Non‐covalent LSD1 inhibitors with biguanidine (8), bisguanidine (9) and oligoamine (PG‐11144, 10) scaffold.

Figure 5

Novel substrate competitive LSD1 inhibitors with basic guanidinium structure (11) and the in vivo active γ‐pyrone Namoline (12).

Figure 6

Chemical structures of Jumonji demethylase inhibitor scaffolds based on other iron‐dependent enzymes and their optimized derivatives. See text for details and references.

Figure 7

Chemical structures of a disulfiram derivative and hydroxyglutarate as well as Jumonji demethylase inhibitors found from screening natural products libraries and a diverse chemical library. See text for details and references.

Figure 8

Chemical structures of more recently discovered small‐molecule inhibitors of Jumonji domain‐containing demethylases. See text for details and references.

Figure 9

Crystal structure of LSD1‐histone H3 peptide complex (2V1D.pdb). The co‐crystalized substrate analog contains a methionine instead of the methylated Lys4 of H3. The peptide side chains are displayed as dark orange sticks, whereas the FAD cofactor is shown in yellow. Only relevant amino acids are displayed. Amino acids of the histone peptide are labeled using single letter code.

Figure 10

Crystal structure of LSD1 in complex with a covalently bound tranylcypromine derivative (2XAS.pdb). The inhibitor is colored orange whereas the cofactor is colored yellow. The protein backbone is displayed as green ribbon and only relevant amino acids for the interaction are shown.

Figure 11

Superposition of KDM2A (yellow, PDB ID 2YU1), KDM4A (green, PDB ID 2WWJ), KDM6A (magenta, PDB ID 3AVR) and KDM7 (cyan, PDB ID 3U78) of the JmjC domain only (RMSD CA: 1.1Å). The residues chelating the iron ion are represented in sticks and color coded equivalent to their ribbon. The inhibitor N‐oxalylglycine (NOG) and the trimethylated lysine of 3AVR are shown in sticks and colored in magenta.

Figure 12

Close‐up view of the active sites corresponding to Figure 11. Additionally, the αKG cofactor (cyan, 3U78) and the inhibitor O‐benzyl‐N‐(carboxycarbonyl)‐d‐tyrosine (green, 2WWJ) are depicted. The residue labels are ordered according to the different subfamilies KDM2A, KDM4A, KDM6A and KDM7, respectively.