However, compound 7 when used in an acute myeloid leukemia flank xenograft model
at 30 mg/kg/day for 14 days reduced H3K9 methylation, with a 45% reduction of
tumor volume [16].
1.1.2 SAM-Competitive G9a/GLP Inhibitors
So far most of the G9a/GLP inhibitors are non-SAM competitive with limited focus
on the development of SAM-competitive inhibitors [17]. Chaetocin (8, Fig. 1), a
fungal epidithiodiketopiperazine alkaloid, will be discussed in more detail among the
SUV inhibitors. However, 8 inhibits EHMT1 and EHMT2 as well, being at least
tenfold less potent than BIX01294 (1). The selectivity of this compound is debated
controversially in the literature [18]. In 2012, Yuan et al. screened a library of
2-substituted benzimidazoles mimicking SAM. They discovered the G9a
SAM-competitive inhibitors BRD9539 (9, Fig. 1) and BRD4770 (10, Fig. 1), its
methyl ester, as a prodrug [17]. While compound 9 inhibited G9a with an IC 50 of
6.3 μM, it also inhibited EZH2 with a similar potency and NSD1 with a lower potency
(IC 50 : 40 μM). It was, however, selective over other epigenetic methyltransferases
such as SUV39H1, SUV39H2, MLL1, SETD7, SETD8, PRMT1, PRMT3, PRMT5,
and DNMT1. Strangely, by now, the inhibition properties of compound 9 versus GLP
are not reported in the literature.
There are also further G9a/GLP inhibitors described in recent works [19, 20], but
these compounds have been just validated in biochemical assays without extensive
further characterization.
1.2 The H3K9 Methyltransferase SETDB1
SET domain bifurcated 1 (SETDB1, also known as ESET or KMT1E) is a HMT
specifically catalyzing H3K9 methylation in the nucleus [21]. SETDB1 is responsible of transcriptional repression and gene silencing. It is implicated in PML-NB
(nuclear bodies)-associated functions and plays a role in embryonic stem cells.
During embryogenesis and postnatal development, SETDB1 is involved in
X-chromosome inactivation, proviral silencing, differentiation of osteocytes and
chondrocytes [22], and myogenesis. All these different aspects have been recently
well reviewed by Karanth et al. [23]. SETDB1 is considered as an oncogene, and it
has been found dysregulated already in early stages of cancer development. Its
expression increases with cancer progression and invasiveness; indeed SETDB1
overexpression occurs in various cancers such as melanoma, lung cancer, ovarian
cancer, hepatocellular carcinoma, and breast cancer [23]. Nevertheless, it is worth to
remember that SETDB1 is involved also in adipogenesis and obesity (through
PPAR-γ modulation), Huntington’s disease, schizophrenia, and autism [23]. So
far, no selective SETDB1 inhibitors have been reported; however the interest for
targeting SETDB1 in cancer is growing. Currently, non-specific SETDB inhibitors,
Lysine Methyltransferases and Their Inhibitors
129
at 30 mg/kg/day for 14 days reduced H3K9 methylation, with a 45% reduction of
tumor volume [16].
1.1.2 SAM-Competitive G9a/GLP Inhibitors
So far most of the G9a/GLP inhibitors are non-SAM competitive with limited focus
on the development of SAM-competitive inhibitors [17]. Chaetocin (8, Fig. 1), a
fungal epidithiodiketopiperazine alkaloid, will be discussed in more detail among the
SUV inhibitors. However, 8 inhibits EHMT1 and EHMT2 as well, being at least
tenfold less potent than BIX01294 (1). The selectivity of this compound is debated
controversially in the literature [18]. In 2012, Yuan et al. screened a library of
2-substituted benzimidazoles mimicking SAM. They discovered the G9a
SAM-competitive inhibitors BRD9539 (9, Fig. 1) and BRD4770 (10, Fig. 1), its
methyl ester, as a prodrug [17]. While compound 9 inhibited G9a with an IC 50 of
6.3 μM, it also inhibited EZH2 with a similar potency and NSD1 with a lower potency
(IC 50 : 40 μM). It was, however, selective over other epigenetic methyltransferases
such as SUV39H1, SUV39H2, MLL1, SETD7, SETD8, PRMT1, PRMT3, PRMT5,
and DNMT1. Strangely, by now, the inhibition properties of compound 9 versus GLP
are not reported in the literature.
There are also further G9a/GLP inhibitors described in recent works [19, 20], but
these compounds have been just validated in biochemical assays without extensive
further characterization.
1.2 The H3K9 Methyltransferase SETDB1
SET domain bifurcated 1 (SETDB1, also known as ESET or KMT1E) is a HMT
specifically catalyzing H3K9 methylation in the nucleus [21]. SETDB1 is responsible of transcriptional repression and gene silencing. It is implicated in PML-NB
(nuclear bodies)-associated functions and plays a role in embryonic stem cells.
During embryogenesis and postnatal development, SETDB1 is involved in
X-chromosome inactivation, proviral silencing, differentiation of osteocytes and
chondrocytes [22], and myogenesis. All these different aspects have been recently
well reviewed by Karanth et al. [23]. SETDB1 is considered as an oncogene, and it
has been found dysregulated already in early stages of cancer development. Its
expression increases with cancer progression and invasiveness; indeed SETDB1
overexpression occurs in various cancers such as melanoma, lung cancer, ovarian
cancer, hepatocellular carcinoma, and breast cancer [23]. Nevertheless, it is worth to
remember that SETDB1 is involved also in adipogenesis and obesity (through
PPAR-γ modulation), Huntington’s disease, schizophrenia, and autism [23]. So
far, no selective SETDB1 inhibitors have been reported; however the interest for
targeting SETDB1 in cancer is growing. Currently, non-specific SETDB inhibitors,
Lysine Methyltransferases and Their Inhibitors
129