1 Introduction
First discovered in 2000, histone methyltransferases catalyze the methylation of a
number of histone and nonhistone substrates. Protein methylation is a dynamic
process, involved in gene expression, transcriptional regulation, and in many key
steps in cell fate decision. The two major families of histone methyltransferases are
the lysine methyltransferases (KMTs) and the arginine methyltransferases (PRMTs).
The KMTs, in turn, can be divided in two different classes: the SET domain- and the
non-SET domain-containing KMTs. DOT1L is the sole member of the non-SET
KMT family. The SET domain-containing KMTs are classified according to their
sequence similarity into five major families including SUV, SET1, SET2, EZ, and
RIZ families [1]. Aberrant histone/protein methylation patterns have been associated
with various disorders including cancer. In time, there has been a growing interest in
elucidating the functions and probing the therapeutic relevance of these enzymes
[2]. Hence, the research on small-molecule modulators of PMTs to be used as tool
compounds or as drug discovery hits has been very prolific. However, despite the
number of studies on several different lysine methyltransferases, relatively few
selective inhibitors have been identified so far. In this chapter we will focus on the
current progress toward the discovery of small-molecule and peptide-based inhibitors of KMTs.
1.1 The H3K9 Methyltransferases EHMT1 and EHMT2
(GLP and G9a)
Euchromatin histone methyltransferases such as EHMT1 and EHMT2, which are
better known as GLP and G9a, are SET domain-containing methyltransferases
which mono- or di-methylate H3K9 as well as other nonhistone substrates, such as
K373 of the tumor suppressor p53 [3]. EHMTs are responsible for transcriptional
repression and activation via the formation of a heterodimeric complex during
germ cell formation, embryogenesis, and cardiac morphogenesis [4]. G9a is
known to be overexpressed across different cancers, such as leukemia, prostate,
lung or liver cancer, where its overexpression was associated with poor prognosis
[5]. The reduction of G9a expression diminished cell proliferation, migration, and
invasion of lung and breast cancer cells in vitro and suppressed tumor growth and
metastasis in vivo [3]. Renneville et al. proved that G9a or GLP knockdown
increased the expression of γ-globin genes leading to an augmented number of
cells expressing hemoglobin F (HbF). This finding could be an interesting starting
point for a new therapy of sickle cell disease via expressing hemoglobin F (HbF), as
increased HbF levels are a well-validated strategy for sickle cell disease (SCD)
treatment [6].
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G. Stazi et al.
First discovered in 2000, histone methyltransferases catalyze the methylation of a
number of histone and nonhistone substrates. Protein methylation is a dynamic
process, involved in gene expression, transcriptional regulation, and in many key
steps in cell fate decision. The two major families of histone methyltransferases are
the lysine methyltransferases (KMTs) and the arginine methyltransferases (PRMTs).
The KMTs, in turn, can be divided in two different classes: the SET domain- and the
non-SET domain-containing KMTs. DOT1L is the sole member of the non-SET
KMT family. The SET domain-containing KMTs are classified according to their
sequence similarity into five major families including SUV, SET1, SET2, EZ, and
RIZ families [1]. Aberrant histone/protein methylation patterns have been associated
with various disorders including cancer. In time, there has been a growing interest in
elucidating the functions and probing the therapeutic relevance of these enzymes
[2]. Hence, the research on small-molecule modulators of PMTs to be used as tool
compounds or as drug discovery hits has been very prolific. However, despite the
number of studies on several different lysine methyltransferases, relatively few
selective inhibitors have been identified so far. In this chapter we will focus on the
current progress toward the discovery of small-molecule and peptide-based inhibitors of KMTs.
1.1 The H3K9 Methyltransferases EHMT1 and EHMT2
(GLP and G9a)
Euchromatin histone methyltransferases such as EHMT1 and EHMT2, which are
better known as GLP and G9a, are SET domain-containing methyltransferases
which mono- or di-methylate H3K9 as well as other nonhistone substrates, such as
K373 of the tumor suppressor p53 [3]. EHMTs are responsible for transcriptional
repression and activation via the formation of a heterodimeric complex during
germ cell formation, embryogenesis, and cardiac morphogenesis [4]. G9a is
known to be overexpressed across different cancers, such as leukemia, prostate,
lung or liver cancer, where its overexpression was associated with poor prognosis
[5]. The reduction of G9a expression diminished cell proliferation, migration, and
invasion of lung and breast cancer cells in vitro and suppressed tumor growth and
metastasis in vivo [3]. Renneville et al. proved that G9a or GLP knockdown
increased the expression of γ-globin genes leading to an augmented number of
cells expressing hemoglobin F (HbF). This finding could be an interesting starting
point for a new therapy of sickle cell disease via expressing hemoglobin F (HbF), as
increased HbF levels are a well-validated strategy for sickle cell disease (SCD)
treatment [6].
126
G. Stazi et al.