1.1.1 Non-SAM-Competitive G9a/GLP Inhibitors
In 2007, BIX01294 (1, Fig. 1), possessing three subunits, the quinazoline, the
piperidine, and the diazepane one, was identified via a high-throughput screening
approach. This compound was the first reported selective small-molecule inhibitor of
G9a and GLP, exhibiting an IC 50 of 1.9 μM for G9a and 0.7 μM for GLP [7]. With the
aid of the BIX-GLP crystal structure, an unoccupied tunnel space, normally hosting
the substrate histone lysine (H3K9), has been identified, allowing the extension of the
molecule into the aforementioned tunnel to achieve more specific and potent inhibitors. Liu et al. extended at first the methyl ether substituent at C-7 to a three-carbon
chain terminating with a dimethyl amine, leading to UNC0224 (2, Fig. 1), which was
fivefold more potent in an enzyme-based assay than the parent compound 1.
The same research group continued to investigate on the 7-position of the
quinazoline moiety, not only by varying the linker size but also by using different
aliphatic and alicyclic terminal groups [8]. This study yielded UNC0321 (3, Fig. 1)
being a nanomolar inhibitor. Compound 1 was found to be rather GLP-specific, while
both compounds 2 and 3 possess a slightly higher specificity toward G9a. Although the
aforementioned EHMT inhibitors were very potent in enzyme-based assays, they lack
desirable drug-like properties, displaying also metabolic issues. To address these
problems, Liu et al. continued their med-chem optimization by modifying the C-2,
C-4, and C-7 positions with numerous chemically different substituents [9]. The most
advanced compound from this study, UNC0638 (4, Fig. 1), features at the C-7 a side
chain. So far, this compound is the most deeply studied G9a/GLP inhibitor present in
the literature, being 600-fold selective over other epigenetic and non-epigenetic targets.
N
N
N
HN
O
O
N
N
N
N
N
HN
O
O
N
CH 3
N
N
N
N
HN
O
O
N
N
N
N
N
HN
O
O
N
N
O
N
N
N
N
HN
O
O
N
N
F
F
1, BIX01294
G9a IC 50 : 1.9 M
GLP IC 50 : 0.7 M
2, UNC0224
G9a IC 50 : 15 nM
3, UNC0321
G9a K i : 63 pM
4, UNC0638
G9a IC 50 : 15 nM
GLP IC 50 : 19 nM
5, UNC0642
G9a IC 50 < 2.5 nM
N
N
N
H
HN
N
O
O
6, MS012
GLP IC 50 : 7 nM
N
NH 2
O
N
O
7, A-366
G9a IC 50 : 3.3 nM
GLP IC 50 : 38 nM
8, Chaetocin
SUV39 IC 50 : 0.6 M
N
N
O
HO
NH
O
9, BRD9539
G9a IC 50 : 6.3 M
NSD1 IC 50 : 40 M
N
N
O
O
NH
O
10, BRD4770
O
HO
S S
N
N
H
N
N
H
N
OH
S
S N
O
O
O
Fig. 1 H3K4 methyltransferases G9a/GLP and SUV39 inhibitors
Lysine Methyltransferases and Their Inhibitors
127
In 2007, BIX01294 (1, Fig. 1), possessing three subunits, the quinazoline, the
piperidine, and the diazepane one, was identified via a high-throughput screening
approach. This compound was the first reported selective small-molecule inhibitor of
G9a and GLP, exhibiting an IC 50 of 1.9 μM for G9a and 0.7 μM for GLP [7]. With the
aid of the BIX-GLP crystal structure, an unoccupied tunnel space, normally hosting
the substrate histone lysine (H3K9), has been identified, allowing the extension of the
molecule into the aforementioned tunnel to achieve more specific and potent inhibitors. Liu et al. extended at first the methyl ether substituent at C-7 to a three-carbon
chain terminating with a dimethyl amine, leading to UNC0224 (2, Fig. 1), which was
fivefold more potent in an enzyme-based assay than the parent compound 1.
The same research group continued to investigate on the 7-position of the
quinazoline moiety, not only by varying the linker size but also by using different
aliphatic and alicyclic terminal groups [8]. This study yielded UNC0321 (3, Fig. 1)
being a nanomolar inhibitor. Compound 1 was found to be rather GLP-specific, while
both compounds 2 and 3 possess a slightly higher specificity toward G9a. Although the
aforementioned EHMT inhibitors were very potent in enzyme-based assays, they lack
desirable drug-like properties, displaying also metabolic issues. To address these
problems, Liu et al. continued their med-chem optimization by modifying the C-2,
C-4, and C-7 positions with numerous chemically different substituents [9]. The most
advanced compound from this study, UNC0638 (4, Fig. 1), features at the C-7 a side
chain. So far, this compound is the most deeply studied G9a/GLP inhibitor present in
the literature, being 600-fold selective over other epigenetic and non-epigenetic targets.
N
N
N
HN
O
O
N
N
N
N
N
HN
O
O
N
CH 3
N
N
N
N
HN
O
O
N
N
N
N
N
HN
O
O
N
N
O
N
N
N
N
HN
O
O
N
N
F
F
1, BIX01294
G9a IC 50 : 1.9 M
GLP IC 50 : 0.7 M
2, UNC0224
G9a IC 50 : 15 nM
3, UNC0321
G9a K i : 63 pM
4, UNC0638
G9a IC 50 : 15 nM
GLP IC 50 : 19 nM
5, UNC0642
G9a IC 50 < 2.5 nM
N
N
N
H
HN
N
O
O
6, MS012
GLP IC 50 : 7 nM
N
NH 2
O
N
O
7, A-366
G9a IC 50 : 3.3 nM
GLP IC 50 : 38 nM
8, Chaetocin
SUV39 IC 50 : 0.6 M
N
N
O
HO
NH
O
9, BRD9539
G9a IC 50 : 6.3 M
NSD1 IC 50 : 40 M
N
N
O
O
NH
O
10, BRD4770
O
HO
S S
N
N
H
N
N
H
N
OH
S
S N
O
O
O
Fig. 1 H3K4 methyltransferases G9a/GLP and SUV39 inhibitors
Lysine Methyltransferases and Their Inhibitors
127