SAM-competitive inhibitor, able to reduce H3K27 methylation levels in cells and to
induce apoptosis in Y641N-mutant large B-cell lymphoma [48].
The dual inhibitor 16 was proved to efficiently arrest cell proliferation
MLL-rearranged leukemia [49] ex vivo and in vivo, while the selective EZH2 inhibitor compound 13 was not as effective. Importantly, these data raise the question
around the possibility and the need of simultaneously targeting EZH1 and EZH2 and
call for deeper investigation about the still misty EZH1, its functions, and its relation
with EZH2. Interestingly, compound 17 (Fig. 2) is the sole potent EZH2i where the
dimethylpyridone was efficiently replaced with a 2,2,6,6-tetramethylpiperidine.
Compound 17 proved effective in KARPAS-422 lymphoma cells [50], but its poor
PK properties did not allow further in vivo evaluation. CPI-360 showed a good
activity profile in the biochemical assays (WT-EZH2 IC 50 : 0.5 nM) as well as in a
KARPAS-422 mouse xenograft model [51]. More recently, an optimization study on
this compound led to the identification of CPI-1205 (18, Fig. 2), a highly potent
(biochemical IC 50 : 2 nM, cellular EC 50 : 32 nM) and selective EZH2 inhibitor.
Vaswani et al. also disclosed the co-crystal structure of compound 18 bound to the
human PRC2 complex. This compound showed once again a potent antitumor
N
N
N
HO
HO
OH
NH 2
11, DZNep
SAH inhibitor
N
N
O
NH
N
O
NH
O
12, EPZ005687
K i : 24 nM
O
NH
NH
O
N
O
20, EBI-2511
IC 50 : 4 nM
N
O
NH
NH
O
N
N
HN
13, GSK126
K i : 0.5-3 nM
N
N
O
NH
NH
O
N
14, GSK343
IC 50 : 4 nM
N
N
O
N
N
N
Cl
H
N
O
HN
17
IC 50 : 32 nM
N
O
NH
N
F
NH
O
O
18, CPI-1205
IC 50 : 2 nM
N
N
NH
O
NH
O
15, EI1
IC 50 : 15 nM
N
N
NH
O
NH
O
N
N
N
16, UNC1999
EZH2 IC 50 : 2 nM
EZH1 IC 50 : 45 nM
F
F
O
NH
NH
O
N
N
O
O
19, EPZ-6438 Tazemetostat
K i : 2.5 nM
O
N
O
NH
NH
O
21, (R)-OR-S1 X=Br
EZH1 IC 50 : 7.4 nM, EZH2 IC 50 : 10 nM
22, (R)-OR-S2 X=Cl
EZH1 IC 50 : 8.4 nM, EZH2 IC 50 : 2.5 nM
X
O
O
N
Fig. 2 An overview on the
most widely reported EZH2
inhibitors
132
G. Stazi et al.
induce apoptosis in Y641N-mutant large B-cell lymphoma [48].
The dual inhibitor 16 was proved to efficiently arrest cell proliferation
MLL-rearranged leukemia [49] ex vivo and in vivo, while the selective EZH2 inhibitor compound 13 was not as effective. Importantly, these data raise the question
around the possibility and the need of simultaneously targeting EZH1 and EZH2 and
call for deeper investigation about the still misty EZH1, its functions, and its relation
with EZH2. Interestingly, compound 17 (Fig. 2) is the sole potent EZH2i where the
dimethylpyridone was efficiently replaced with a 2,2,6,6-tetramethylpiperidine.
Compound 17 proved effective in KARPAS-422 lymphoma cells [50], but its poor
PK properties did not allow further in vivo evaluation. CPI-360 showed a good
activity profile in the biochemical assays (WT-EZH2 IC 50 : 0.5 nM) as well as in a
KARPAS-422 mouse xenograft model [51]. More recently, an optimization study on
this compound led to the identification of CPI-1205 (18, Fig. 2), a highly potent
(biochemical IC 50 : 2 nM, cellular EC 50 : 32 nM) and selective EZH2 inhibitor.
Vaswani et al. also disclosed the co-crystal structure of compound 18 bound to the
human PRC2 complex. This compound showed once again a potent antitumor
N
N
N
HO
HO
OH
NH 2
11, DZNep
SAH inhibitor
N
N
O
NH
N
O
NH
O
12, EPZ005687
K i : 24 nM
O
NH
NH
O
N
O
20, EBI-2511
IC 50 : 4 nM
N
O
NH
NH
O
N
N
HN
13, GSK126
K i : 0.5-3 nM
N
N
O
NH
NH
O
N
14, GSK343
IC 50 : 4 nM
N
N
O
N
N
N
Cl
H
N
O
HN
17
IC 50 : 32 nM
N
O
NH
N
F
NH
O
O
18, CPI-1205
IC 50 : 2 nM
N
N
NH
O
NH
O
15, EI1
IC 50 : 15 nM
N
N
NH
O
NH
O
N
N
N
16, UNC1999
EZH2 IC 50 : 2 nM
EZH1 IC 50 : 45 nM
F
F
O
NH
NH
O
N
N
O
O
19, EPZ-6438 Tazemetostat
K i : 2.5 nM
O
N
O
NH
NH
O
21, (R)-OR-S1 X=Br
EZH1 IC 50 : 7.4 nM, EZH2 IC 50 : 10 nM
22, (R)-OR-S2 X=Cl
EZH1 IC 50 : 8.4 nM, EZH2 IC 50 : 2.5 nM
X
O
O
N
Fig. 2 An overview on the
most widely reported EZH2
inhibitors
132
G. Stazi et al.