Abstract Due to their prevalent role in epigenetic gene regulation, methyllysine
and methylarginine domain readers have emerged as potential drug targets for smallmolecule intervention. Within this book chapter, the biological role and the associated development of potent small molecules inhibiting the protein-protein interaction
of methyllysine readers (Tudor, malignant brain tumor, chromo-, and PHD domain)
will be discussed. The druggability of these readers and thus their potential to serve
as targets for small-molecule ligands will be evaluated critically. Those domains
(PWWP, WD40, ankyrin repeats, and ADD domains) which are not yet targeted
will be evaluated for their biological actions and eventual therapeutic implications.
To sum up, a comprehensive review of the state of the art for all relevant methylreaders and their inhibitors if present will be given from a medicinal chemistry
standpoint of view.
Keywords Chromatin domain, Epigenetic readers, Inhibitors, Malignant brain
tumor domain, Methyl-readers, PHD domain, Royal Family domain, Tudor domain
1 Introduction
Methylation is perhaps the most versatile of all histone posttranslational modifications (PTMs). It can occur on both lysine and arginine residues, and each of
them has three possible methylation states. Lysine can be mono (Kme1)-, di
(Kme2)-, or trimethylated (Kme3) on its ε-amino group (Fig. 1). The dynamic
methylation state of lysine residues is controlled by a balance in the activity of
lysine methyltransferases (KMTs) [1], which transfer methyl groups from
S-adenosylmethionine (SAM) to the lysine residue, and demethylases (KDMs),
which remove methyl groups. Unlike lysine acetylation, methylation does not alter
the charge of the amino acid side chain. Instead, there is only a gradual increase in
size and lipophilicity from the non-methylated state to mono-, di-, and trimethylation
[2–4]. In contrast to lysines, arginines are only mono- (Rme1) or dimethylated, but
the dimethylation can be symmetrical (Rme2s) or asymmetrical (Rme2a; Fig. 1)
[2, 5]. The three types of arginine methylation are catalyzed by a family of nine
SAM-dependent enzymes called the protein arginine methyltransferases (PRMTs).
Arginine demethylation activity has been reported for the JmjC domain-containing
protein JMJD6 [6], even if this has been challenged by other studies [7]. The
methylation of arginine changes its shape, does not alter the charge, but removes
potential hydrogen bond donors, which would potentially inhibit certain interactions
[8]. On the other hand, the methylation of arginine residues can also increase
their affinity to aromatic rings in cation-π interactions, thus promoting other
interactions [9].
A significant part of the biological outcome of Lys and/or Arg methylation is
quite probably driven by specific reader proteins, which not only recognize the
methylation marks but also distinguish between the various methylation states
and result in downstream events, including the addition and removal of additional
PTMs, chromatin condensation, or recruitment of transcriptional machinery leading
340
G. Sbardella
and methylarginine domain readers have emerged as potential drug targets for smallmolecule intervention. Within this book chapter, the biological role and the associated development of potent small molecules inhibiting the protein-protein interaction
of methyllysine readers (Tudor, malignant brain tumor, chromo-, and PHD domain)
will be discussed. The druggability of these readers and thus their potential to serve
as targets for small-molecule ligands will be evaluated critically. Those domains
(PWWP, WD40, ankyrin repeats, and ADD domains) which are not yet targeted
will be evaluated for their biological actions and eventual therapeutic implications.
To sum up, a comprehensive review of the state of the art for all relevant methylreaders and their inhibitors if present will be given from a medicinal chemistry
standpoint of view.
Keywords Chromatin domain, Epigenetic readers, Inhibitors, Malignant brain
tumor domain, Methyl-readers, PHD domain, Royal Family domain, Tudor domain
1 Introduction
Methylation is perhaps the most versatile of all histone posttranslational modifications (PTMs). It can occur on both lysine and arginine residues, and each of
them has three possible methylation states. Lysine can be mono (Kme1)-, di
(Kme2)-, or trimethylated (Kme3) on its ε-amino group (Fig. 1). The dynamic
methylation state of lysine residues is controlled by a balance in the activity of
lysine methyltransferases (KMTs) [1], which transfer methyl groups from
S-adenosylmethionine (SAM) to the lysine residue, and demethylases (KDMs),
which remove methyl groups. Unlike lysine acetylation, methylation does not alter
the charge of the amino acid side chain. Instead, there is only a gradual increase in
size and lipophilicity from the non-methylated state to mono-, di-, and trimethylation
[2–4]. In contrast to lysines, arginines are only mono- (Rme1) or dimethylated, but
the dimethylation can be symmetrical (Rme2s) or asymmetrical (Rme2a; Fig. 1)
[2, 5]. The three types of arginine methylation are catalyzed by a family of nine
SAM-dependent enzymes called the protein arginine methyltransferases (PRMTs).
Arginine demethylation activity has been reported for the JmjC domain-containing
protein JMJD6 [6], even if this has been challenged by other studies [7]. The
methylation of arginine changes its shape, does not alter the charge, but removes
potential hydrogen bond donors, which would potentially inhibit certain interactions
[8]. On the other hand, the methylation of arginine residues can also increase
their affinity to aromatic rings in cation-π interactions, thus promoting other
interactions [9].
A significant part of the biological outcome of Lys and/or Arg methylation is
quite probably driven by specific reader proteins, which not only recognize the
methylation marks but also distinguish between the various methylation states
and result in downstream events, including the addition and removal of additional
PTMs, chromatin condensation, or recruitment of transcriptional machinery leading
340
G. Sbardella