SAH derived potent and selective EZH2 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2015.02.017

A series of novel enhancer of zeste homolog 2 (EZH2) inhibitors was designed based on the chemical structure of the histone methyltransferase (HMT) inhibitor SAH (S-adenosyl-l-homocysteine). These nucleoside-based EZH2 inhibitors blocked the methylation of nucleosomes at H3K27 in biochemical assays employing both WT PRC2 complex as well as a Y641N mutant PRC2 complex. The most potent compound, 27, displayed IC₅₀'s against both complexes of 270 nM and 70 nM, respectively. To our knowledge, compound 27 is the most potent SAH-derived inhibitor of the EZH2 PRC2 complex yet identified. This compound also displayed improved potency, lipophilic efficiency (LipE), and selectivity profile against other lysine methyltransferases compared with SAH.

Full text of DOI:10.1016/j.bmcl.2015.02.017

Bioorganic & Medicinal Chemistry Letters 25 (2015) 1532–1537
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
SAH derived potent and selective EZH2 inhibitors
a
a
a
b
b
Pei-Pei Kung a, , Buwen Huang , Luke Zehnder , John Tatlock , Patrick Bingham , Cody Krivacic ,
⇑
Ketan Gajiwala a, Wade Diehl a, Xiu Yu a, Karen A. Maegley b
a Oncology Chemistry, Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr., San Diego, CA 92121, USA
b Oncology Research Unit, Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr., San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel enhancer of zeste homolog 2 (EZH2) inhibitors was designed based on the chemical
Received 12 December 2014
Revised 4 February 2015
Accepted 9 February 2015
Available online 17 February 2015
structure of the histone methyltransferase (HMT) inhibitor SAH (S-adenosyl-L-homocysteine). These
nucleoside-based EZH2 inhibitors blocked the methylation of nucleosomes at H3K27 in biochemical
assays employing both WT PRC2 complex as well as a Y641N mutant PRC2 complex. The most potent
compound, 27, displayed IC50’s against both complexes of 270 nM and 70 nM, respectively. To our knowl-
edge, compound 27 is the most potent SAH-derived inhibitor of the EZH2 PRC2 complex yet identified.
This compound also displayed improved potency, lipophilic efficiency (LipE), and selectivity profile
against other lysine methyltransferases compared with SAH.
Keywords:
EZH2
SAH
Nucleoside
Homology model
Ó 2015 Elsevier Ltd. All rights reserved.
Epigenetics involves the study of stably heritable phenotypes
that result from changes in a chromosome without alterations in
the DNA sequence.1a,b Such changes include histone modification,
which can alter chromatin structure and reveal docking sites for
a variety of proteins including chromatin remodeling proteins
and transcription factor complexes. These histone changes thus
contribute to the regulation of transcription, repair, and replication
across a given genome. Methylation of specific lysine or arginine
residues within the N-terminal tails of histone proteins are a key
component of epigenetic gene regulation.2 Consequently, alter-
ations in the expression or activity of enzymes responsible for
establishing, maintaining, and regulating histone methylation can
lead to the initiation and maintenance of cancer.3a,b Recently, the
first examples of histone methyltransferase and demethylase
inhibitors have entered clinical trials for the treatment of cancer.4a,b
The polycomb repressive complex 2 (PRC2) which contains the
EZH2 (enhancer of zeste homolog 2) methyltransferase has been
shown to repress gene transcription through tri-methylation of
Histone H3 lysine 27 (H3K27).5a–c Recently, somatic activating
mutations (such as Y641N) in the catalytic (SET) domain of EZH2
have been identified in follicular lymphoma and the
germinal-center B-cell (GCB) subtype of diffuse large B-cell lym-
phoma (DLBCL), leading to increased levels of trimethylated
its catalytic product S-adenosyl-L-homocysteine (SAH) and the nat-
ural product sinefungin, have been reported as promiscuous inhi-
bitors of various methyltransferases.7 In 2012, Epizyme reported
an aza-SAH analog which exhibits IC50s of 9 lM and 4 lM against
the WT and Y641N mutant EZH2–containing PRC2 complexes,
respectively.8 Our internal program aimed to improve the affinity
of this class of nucleoside inhibitors toward the EZH2 PRC2 com-
plex and to explore the selectivity of these analogs against other
lysine histone methyl transferases (KHMTs).
We developed a biochemical assay which assessed the ability of
the test compounds to inhibit EZH2-mediated methyl transfer
using isolated oligonucleosomes as the substrate. Since there was
no available crystal structural information to guide compound
optimization, we used a homology model9 containing cofactor
product (SAH) to guide our initial SAR exploration. This homology
model was initially built using MLL1 (PDBID: 2w5z)10 and SuVar
3-9 (PDBID: 2r3a)11 SET domain structures and subsequently
refined using recently reported EZH2 SET domain crystal struc-
tures12a,b (inactive conformation). However, this model lacked
other PRC2 protein components and only contained the EZH2 SET
domain. The binding mode of SAH was putatively located based
on the binding of SAH in the MLL1 crystal structure10 (Fig. 1). In
this model, three amino acid residues, His689, Asn688, and
Trp624 in the SET domain form key interactions with SAH
(Fig. 1). One of the protons of the N6-amino group and the N7
endocyclic nitrogen atom of the adenine ring form hydrogen bonds
with the backbone carbonyl and amide moieties of His689, respec-
tively. The model also presents an unfilled space next to the ade-
nine moiety near N-6 amino group. The amino group of the
H3K27.6 S-adenosyl-
L-methionine (SAM) serves as the endogenous
co-substrate and binds to the EZH2 SET domain to enable transfer
of a methyl group to the H3K27 substrate. Analogs of SAM, such as
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.bmcl.2015.02.017
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

P.-P. Kung et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1532–1537
1533
SAH
6NH2
NH2
N
N
N7
HOOC
O
S
N
HO
OH
Figure 1. EZH2 SET domain homology model and SAH binding. Hydrogen bonds are indicated with dashed red lines. Protein residues which form hydrogen bonds with SAH
are highlighted in stick.
Table 1
homocysteine moiety forms key hydrogen bonds with the Asn688
side chain and carbonyl moiety of the Trp624. The carbonyl group
of the carboxylic acid moiety present in SAH forms a hydrogen
bond with Trp624 backbone nitrogen atom. Therefore, a series of
six SAH analogs was synthesized to probe the structure determi-
nants of the SAH binding.
In order to confirm the key interactions with the amino and car-
boxylic acid groups present in SAH observed in other available
crystal structures (Fig. 1), we synthesized compounds 2 and 3
which, respectively, eliminated the amino and carboxylic acid moi-
eties (Table 1). These two compounds displayed no inhibition at
Structure–activity relationships of SAH
R3
NH
R1
N
N
N
R2
C2
O
X
N
HO
OH
R1
R2
R3
WT enzyme IC50
M)
a
Compd# C2
stereochem
X
the maximum concentration tested (20 lM). These results indicat-
(
l
ed the importance of these two groups for SAH interaction with the
EZH2 SET domain. We also replaced the sulfur atom in SAH with an
N-methyl group (compound 4, Table 1) and observed that this
transformation resulted in a total loss of potency. In addition, we
explored the substitution of the N6-amino group with both small
and large hydrophobic moieties to explore the empty space sur-
rounded by the N6-amino group presented in the homology model.
These modifications included methyl, isopropyl, and benzyl groups
(compounds 5–7, Table 1), and all of these compounds resulted in
complete loss of potency. This outcome was not consistent with
the homology model, but there are variations in the protein struc-
ture close to this amino group which may account for these results.
A few amide-containing compounds were then designed and
synthesized to see if both oxygen atoms of the SAH carboxylic acid
moiety formed key interactions with the EZH2 enzyme. Tertiary
amides containing small and large hydrophobic moieties, such as
dimethyl, cyclopentyl, and isoindoline groups (compounds 8–10,
Table 2) all completely lost potency. Secondary amides containing
n-butyl, cyclopropyl, phenyl, or pyrazole moieties bridged by a
methylene linker regained potency (compounds 11a,b–15,
1
2
3
4
5
6
7
S
S
S
S
NH2 CO2H
H
H
H
H
11
5
NA
NA
S
S
S
H
NH2
CO2H
H
NI@20
NI@20
NI@20
l
l
l
l
l
l
M
M
M
M
M
M
NCH3 NH2 CO2H
S
S
S
NH2 CO2H CH3 NI@20
NH2 CO2H i-Pr NI@20
NH2 CO2H Bn
S
NI@20
NA: not applicable.
NI: no measurable inhibition.
a
Values are the average of at least two independent measurements SD.
Table 2). However, these molecules all displayed about 5 fold
potency loss compared with SAH (Table 2). One of the
pyrazole-containing compounds (15, Table 2) was of interest for
further exploration based on examination of available space sug-
gested by our model. Accordingly, shortening or extending the
methylene linker present in compound 15 resulted in loss of
potency (compare compounds 16 and 17 with compound 15,
Table 2). In Table 3, various N-substituted pyrazoles were intro-
duced to investigate the potency effect of lipophilic moieties

1534
P.-P. Kung et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1532–1537
Table 2
Table 3
Structure–activity relationships of secondary and tertiary amides of SAH
Structure–activity relationships of N-substituted pyrazoles
NH2
NH2
NH2
NH2
N
N
N
N
R
R
N
N
C2
O
O
S
N
S
N
O
O
HO
OH
HO
OH
a
Compd#
C2 stereochem
R
WT enzyme IC50
11
(
lM)
Compd#
R
WT enzyme
Y641N enzyme
IC50 (lM)
a
b
IC50
(
lM)
1
S
OH
5
1
OH
11
5
1.9 0.3
N
8
9
R/S (1:1)
R/S (1:1)
NI@20
NI@20
l
l
M
M
N
H
N
15
50 20
ND
N
N
N
H
N
18
19
20
24
28
5
9
ND
Ph
F
N
N
10
R/S (1:1)
R/S (1:1)
NI@20
l
M
N
N
H
ND
N
N
H
11a
24
19
1
6
N
H
N
1.4 0.1
0.6 0.2
N
N
H
ND: not determined.
11b
S
a,b
Values are the average of at least two independent measurements SD.
N
H
12
13
S
S
60 20
and provided more SAR information. The 4-fluorophenyl moiety
present in compound 20 was replaced with a more polar fused
pyrazole–piperidine moiety (21) which lost about 50 fold potency.
Introducing a benzyl group on the piperidine nitrogen regained 5
fold potency (compare 22 with 21, Table 4). We then investigated
the lipophilic space surrounded the pyrazole moiety of 20 by incor-
porating substituents on the carbon atom adjacent to the pyrazole
nitrogen (compounds 23 to 27). While comparing compound 23
with 24, the IC50 value of the latter molecule improved by 10 fold
(Table 4). This result indicated that the pyrazole NH moiety (tau-
tomer unknown) was engaged in a hydrogen bond with the pro-
tein. Further substituting the cyclobutyl ring present in 24 with
either t-butyl (compound 25) or methylenemethoxy (compound
26) moieties all resulted in loss of potency. However, replacement
of the cyclobutyl with a phenyl moiety (compound 27, Table 4)
greatly improved the potency relative to both compound 20 and
SAH.
N
H
120 30
N
N
H
14
S
40 20
50 20
N
N
H
N
15
16
S
S
N
N
N
NI@20
NI@20
l
l
M
M
N
H
N
In conclusion, the N6-amino, 50-thio, and S-2 amino moieties
present in SAH are relatively conserved with respect to the inhibi-
tor binding. However, the carboxylic acid moiety could be trans-
formed into a variety of biochemically active secondary amides.
Compound 27 was proven to be a SAM competitive EZH2 inhibitor
(Fig. 2). It displayed potent IC50s against both WT PRC2 complex
and mutant EZH2 Y641N containing PRC2 complex (270 nM and
70 nM, respectively). The measured IC50 value against the WT
PRC2 complex represents a 42-fold potency improvement relative
to that exhibited by the starting SAH molecule. To our knowledge,
compound 27 is the most potent SAH-derived inhibitor of the EZH2
PRC2 complex yet identified. This compound was further profiled
in a screening panel encompassing other KHMTs. As shown in
Table 5, compound 27 displayed improved selectivity relative to
SAH against other lysine HMT enzymes. The molecule also dis-
played potent inhibition of the arginine methyltransferase,
PRMT413 (IC50: 30 nM).
N
17
S
N
H
NI: no measurable inhibition.
a
Values are the average of at least two independent measurements SD.
attached to the heterocycle. Compounds 18 and 19 displayed simi-
lar activity compared with compound 15 by either extending the
ethyl substituent (of 15) to a benzyl moiety (18) or replacing the
ethyl group with a ortho-methyl phenyl group (19) (Table 3).
Compound 20 containing
attached to the pyrazole displayed a biochemical inhibition IC50
of 1.4 M (Table 3). This result represents a 30 fold improvement
a 4-fluorophenyl moiety directly
l
in inhibitory activity relative to compound 15 and about 10 fold
improvement compared with SAH.
We also performed an analysis to determine whether the
described potency improvements also increased lipophilic ligand
efficiency (LipE).14 As shown in Figure 3, compound 27 exhibits
significantly improved LipE relative to SAH as did several other
Based on this encouraging result, we designed and synthesized
more pyrazole-containing amides to further improve the bio-
chemical potency. Several compounds containing commercially
available substituted or fused pyrazole-amides were synthesized

P.-P. Kung et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1532–1537
1535
27 Concentration µM
Table 4
4
Extended structure–activity relationship of substituted-pyrazoles
5
NH2
2.5
1.25
0.63
0.31
0
3
2
1
0
NH2
N
N
R
N
O
S
N
O
HO
OH
0
20
40
60
Compd#
R
WT enzyme
Y641N enzyme
[SAM] µM
a
b
IC50
(
lM)
IC50
(lM)
Figure 2. The mechanism of inhibition for compound 27 with respect to the SAM
co-substrate was evaluated using saturating concentrations of nucleosome sub-
strate, various concentrations of SAM and several different inhibitor concentrations
1
OH
11
5
1.9 0.3
N
(j 0,
0.31,
0.63,
1.25,
2.5,
5 lM). The data are the mean of two
N
H
N
independent measurements; the error bars represent the standard deviation. The
data are fit globally to a competitive inhibition model.
21
22
50 20
ND
N
N
N
H
N
Table 5
8
3
2.8 0.6
Comparison of HMT selectivity between SAH and 27
N
Ph
HMT assay
SAH IC50
M)
27
Ratio SAH IC50/27
IC50
(l
IC50
(
l
M)
% inh. @
10
N
N
H
l
M
N
EZH2
EZH1
G9a
11
5
0.27 0.08
2.1 0.4
>100
41
3
23
24
40 20
ND
6.4 0.7
2.0 0.7
20.0 0.5
EHMT1
MLL
SETD7
SETDB1
SUV39H1
SUV39H2
SUV420H2
SMYD2
0.23 0.03
2.3 0.2
30 10
2.2 0.1
1.2 0.1
>30
18.5 0.7
>100
>100
9.5 0.4
>100
24
4
3
0.12
0.13
N
NI
NI
N
H
HN
HN
3
2
6
1.0 0.2
32
10
7
2
20
NI
NI
>100
>100
0.18 0.03
N
NI: no measurable inhibition.
N
H
25
26
14
3.6 0.3
(low LogD and/or high molecular weight and topological polar sur-
face area (TPSA), especially for 27, and the presence of a large num-
ber of hydrogen bond donors for both SAH and 27) that limit their
access to intracellular compartments. Consistent with this hypoth-
esis, compound 27 displayed poor permeability as measured in an
in vitro assay (cell permeability measured using low efflux Madin–
Darby canine kidney cell line (MDCKII): 1 ꢀ 10ꢁ6 cm/s).15 Realizing
the full potential of these SAH-derived EZH2 inhibitors will thus
require the targeting of physical chemistry space, that is, more con-
sistent with good permeability. Modulating lipophilicity, molecu-
lar weight, TPSA, and/or the number of hydrogen bond donors
may offer the desired improvements.16
SAH was purchased from Aldrich, Inc. Compounds 2 and 3 were
synthesized using methods reported in the literature.17 Compound
4 (aza-SAM) was prepared using the procedure reported by Joce
et al.18 Compounds 5–7 described in Table 1 were synthesized as
racemic mixtures using the method described by Zablocki et al.
and Sebti et al.19,20 Compounds 8 and 10 described in Table 2 were
synthesized as racemic mixtures using a modified literature condi-
N
N
H
HN
O
40 20
ND
N
N
H
HN
27
0.27 0.08
0.07 0.02
ND: not determined.
a,b
Values are the average of at least two independent measurements SD.
compounds described in this work (20 and 24). These examples
illustrate that the potency improvements depicted in Tables 3
and 4 were often realized via efficient utilization of compound
lipophilicity and suggest that the strategy of starting from SAH to
generate selective and potent methyl transferase inhibitors may
have further potential. Unfortunately, neither compound 27 nor
SAH was active in cell-based assays which examined both reduc-
tion of H3K27Me3 level and anti-proliferation effects (max tested
tion via the N-boc protected D,L-homocysteine thiolactone in three
steps.21 A one-pot synthesis strategy of the amide products of com-
pounds 9 and 11a was also developed using a similar synthetic
scope as depicted in Scheme 1. The homocysteine thiolactone
(29) was treated with various amines and the resulting thiol was
then reacted with 28 to yield compounds 9 and 11a. However, this
one-pot synthesis strategy did not work for amines containing
concentration: 100
assays is almost certainly related to physicochemical properties
lM). The absence of activity in cell-based

1536
P.-P. Kung et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1532–1537
electron withdrawing groups, such as 4,4-difluoro-piperidine and
2,2,2-trifluoroethan-1-amine. Therefore, a more general synthesis
for the amide-containing inhibitors described in Tables 3 and 4
was developed as depicted in Scheme 2. Specifically, the single
enantiomer of 11a (11b) was also synthesized using methods
described in Scheme 2 to confirm the chirality of the active com-
pound. In Scheme 2, the synthesis of amide coupling precursor
34 began with a commercially available chiral starting material
30. The amino groups of 30 were protected with boc anhydride
to give 31,22,23 followed by subsequent disulfide reduction using
dithiothreitol (DTT)22 to afford compound 32. Compound 32 was
then condensed with 3324 under basic aqueous conditions to give
34. This entity 34 was employed as a key intermediate for amide
coupling reactions with various amines using HATU or HOBt/BOP
as the coupling agents. For example, compound 34, commercially
available amine 35, HATU, and DIPEA were stirred at room tem-
perature for 12 h. The desired coupling product (36) was
de-protected using trifluoroacetic acid to afford compound 27 after
preparative HPLC purification.
Figure 3. Spotfire plot for compounds in Tables 3 and 4 to compare their potency
and lipophilicity, x-axis: cSFlogD: calculated shake flask logD, y-axis: pIC50 was
calculated from ꢁlog10([proliferation IC50 in M]), LipE line was generated using the
formula: y = x + 4 (for LipE line = 4)
N
NH2
N
NH2
NH2
O
N
O
N
O
RNH2
a, b
R
Cl
N
S
H2N
N
N
+
N
O
S
HO
HO
OH
OH
29
28
9
N
, R=
11a
, R=
HN
Scheme 1. One pot synthesis of racemic compounds 9 and 11a. Reagents and conditions: (a) amines, degassed DMSO, K2CO3(s), 60 °C, 1 h; (b) 4 N NaOH(aq), 80 °C, 0.5 h, 25–
27%.
O
O
NH2
O
HN
O
O
a
HN
O
HO
S
b
HO
S
S
OH
HO
S
OH
SH
O
NH2
O
O
NH
30
O
32
31
O
N
NH2
O
N
Cl
N
O
N
O
O
HN
O
N
33
NH2
32
O
HO
N
S
c
N
O
N
O
O
34
O
NH2
N
NH2
HN
O
35
H
N
O
e
N
HN
N
34
N
27
S
N
d
N
O
HN
HO
OH
36
Scheme 2. Synthesis protected SAH intermediate for amide coupling of compound 27. Reagents and conditions: (a) (Boc)2O, Na2CO3, H2O/dioxane, 0–23 °C, 12 h, 96%; (b)
DTT, DMF/H2O, 50 °C, 12 h; (c) NaOH, MeOH, 60 °C, 12 h, 66%, two steps; (d) HATU, DIPEA, DMF, 23 °C, 12 h, 68.5%; (e) CF3CO2H, H2O, 0 °C, 5 h, 39%.

P.-P. Kung et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1532–1537
1537
Griffith, O. L.; Shah, S.; Zhu, H.; Kimbara, M.; Shashkin, P.; Charlot, J. F.;
Tcherpakov, M.; Corbett, R.; Tam, A.; Varhol, R.; Smailus, D.; Moksa, M.; Zhao,
Y.; Delaney, A.; Qian, H.; Birol, I.; Schein, J.; Moore, R.; Holt, R.; Horsman, D. E.;
Connors, J. M.; Jones, S.; Aparicio, S.; Hirst, M.; Gascoyne, R. D.; Marra, M. A. Nat.
Genet. 2010, 42, 181.
Acknowledgements
We are grateful to Drs. Martin Edwards and Martin Wythes for
helpful discussions during manuscript preparation. We also
acknowledge Jeff Elleraas, Loanne Chung, and Phuong Tran for
purification assistance.
7. Richon, V. M.; Johnston, D.; Sneeringer, C. J.; Jin, L.; Majer, C. R.; Elliston, K.;
Jerva, L. F.; Scott, M. P.; Copeland, R. A. Chem. Biol. Drug Des. 2011, 78, 199.
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Knutson, S. K.; Pollock, R. M. WO2012034132, 2012.
9. Details in Supporting material.
10. Southall, S. M.; Wong, P.-S.; Odho, Z.; Roe, S. M.; Wilson, J. R. Mol. Cell 2009, 33,
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Supplementary data
11. Wu, H.; Min, J.; Lunin, V. V.; Antoshenko, T.; Dombrovski, L.; Zeng, H.;
Allali-Hassani, A.; Campagna-Slater, V.; Vedadi, M.; Arrowsmith, C. H.;
Plotnikov, A. N.; Schapira, M. PLoS 2010, 5, e8570.
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Brown, P. J.; Vedadi, M.; Arrowsmith, C. H.; Schapira, M. PLoS 2013, 8, e83737;
(b) Antonysamy, S.; Condon, B.; Druzina, Z.; Bonanno, J. B.; Gheyi, T.; Zhang, F.;
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.02.
017.
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