Structure-activity relationship studies of SETD8 inhibitors

Article abstract of DOI:10.1039/c4md00317a

SETD8 (also known as SET8, PR-SET7, or KMT5A (lysine methyltransferase 5A)) is the only known lysine methyltransferase that catalyzes the monomethylation of histone H4 lysine 20 (H4K20). In addition to H4K20, SETD8 monomethylates non-histone substrates such as the tumor suppressor p53 and the proliferating cell nuclear antigen (PCNA). Because of its role in regulating diverse biological processes, SETD8 has been pursued as a potential therapeutic target. We recently reported the first substrate-competitive SETD8 inhibitor, UNC0379 (1), which is selective for SETD8 over 15 other methyltransferases. We characterized this inhibitor in a battery of biochemical and biophysical assays. Here we describe our comprehensive structure-activity relationship (SAR) studies of this chemical series. In addition to 2- and 4-substituents, we extensively explored 6- and 7-substituents of the quinazoline scaffold. These SAR studies led to the discovery of several new compounds, which displayed similar potencies as compound 1 and interesting SAR trends. This journal is

Full text of DOI:10.1039/c4md00317a

MedChemComm
View Article Online
View Journal | View Issue
CONCISE ARTICLE
Structure–activity relationship studies of SETD8
inhibitors†‡
Cite this: Med. Chem. Commun., 2014,
5, 1892
a
d
a
a
d
abc
*
Anqi Ma, Wenyu Yu, Yan Xiong, Kyle V. Butler, Peter J. Brown and Jian Jin
SETD8 (also known as SET8, PR-SET7, or KMT5A (lysine methyltransferase 5A)) is the only known lysine
methyltransferase that catalyzes the monomethylation of histone H4 lysine 20 (H4K20). In addition to
H4K20, SETD8 monomethylates non-histone substrates such as the tumor suppressor p53 and the
proliferating cell nuclear antigen (PCNA). Because of its role in regulating diverse biological processes,
SETD8 has been pursued as a potential therapeutic target. We recently reported the first substrate-
competitive SETD8 inhibitor, UNC0379 (1), which is selective for SETD8 over 15 other methyltransferases.
We characterized this inhibitor in a battery of biochemical and biophysical assays. Here we describe our
comprehensive structure–activity relationship (SAR) studies of this chemical series. In addition to 2- and
4-substituents, we extensively explored 6- and 7-substituents of the quinazoline scaffold. These SAR
studies led to the discovery of several new compounds, which displayed similar potencies as compound
1 and interesting SAR trends.
Received 21st July 2014
Accepted 16th September 2014
DOI: 10.1039/c4md00317a
www.rsc.org/medchemcomm
known PKMT that catalyzes the monomethylation of histone H4
lysine 20 (H4K20).36–38 Monomethylation of H4K20 (H4K20me)
Introduction
and SETD8 has been implicated in DNA damage response and
cell cycle progression.38 In addition, SETD8 promotes epithe-
lial–mesenchymal transition (EMT) by physically associating
with TWIST, a master regulator of EMT.39 SETD8 also mono-
methylates lysine 382 (K382) of the tumor suppressor p53 and
lysine 248 (K248) of the proliferating cell nuclear antigen
(PCNA) and plays a potential role in human carcinogenesis.40,41
We recently reported UNC0379 (1) as the rst substrate-
competitive small-molecule inhibitor of SETD8 (Fig. 1).42
Compound 1 is active in multiple biochemical (e.g., radioactive
methyl transfer and microuidic capillary electrophoresis) and
biophysical (e.g., isothermal titration calorimetry and surface
plasmon resonance) assays, and importantly, selective for
SETD8 over 15 other methyltransferases.42 The only other
known selective inhibitor of SETD8 is a marine natural product
nahuoic acid A, which is competitive with the co-factor S-ade-
nosyl-L-methionine (SAM) (Fig. 1).21 In this article, we describe
Post-translational modications (PTMs) of histones are critical
in regulating gene expression and transcription.1–3 Among a
myriad of PTMs, histone lysine methylation has been recog-
nized as a major mechanism in chromatin regulation. Histone
lysine methylation typically takes place at the N-terminal tails of
core histone proteins (H3, H4, H2A, and H2B) and is catalyzed
by protein lysine methyltransferases (PKMTs). It is worth noting
that PKMTs also methylate many non-histone substrates.4
PKMTs have been increasingly recognized as a class of
potential therapeutic targets by the medicinal chemistry and
drug discovery community. Consequently, a number of selective
inhibitors of PKMTs have been discovered during recent
years.5–31 Related to PKMTs, protein arginine methyl-
transferases (PRMTs) catalyze the methylation of arginine resi-
dues of histone and non-histone proteins.32 A number of
selective inhibitors of PRMTs have also been reported.33–35
SETD8 (also known as SET8, PR-SET7, or KMT5A (lysine
methyltransferase 5A)), rst characterized in 2002, is the only
aDepartment of Structural and Chemical Biology, Icahn School of Medicine at Mount
Sinai, New York, NY, 10029, USA. E-mail: jian.jin@mssm.edu; Tel: +1-212-659-8699
bDepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New
York, NY, 10029, USA
cDepartment of Pharmacology and Systems Therapeutics, Icahn School of Medicine at
Mount Sinai, New York, NY, 10029, USA
dStructural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7,
Canada
† This article is part of the MedChemComm “Epigenetics” themed issue.
‡ Electronic supplementary information (ESI) available: Synthesis procedures,
characterization data, and biochemical assays. See DOI: 10.1039/c4md00317a
Fig. 1 Structures of the known selective inhibitors of SETD8.
1892 | Med. Chem. Commun., 2014, 5, 1892–1898
This journal is © The Royal Society of Chemistry 2014

View Article Online
Concise Article
MedChemComm
our comprehensive structure–activity relationship (SAR) studies
of the quinazoline template represented by compound 1, which
resulted in the discovery of interesting SAR trends and novel
analogs with similar potencies as compound 1.
Scheme 1 Typical synthesis of 2,4-diamino-6,7-dimethoxyquinazo-
lines. Reagents and conditions: (a) R1 amines, THF, N,N-diisopropyl-
ethylamine, room temperature; (b) R2 amines, n-BuOH, DIPEA,
microwave, heat.
Results and discussion
Our strategy for studying the SAR of the UNC0379 series was to
extensively explore the 2-, 4-, 6-, and 7-substituents (Fig. 2). We
previously reported the initial SAR results of the 2- and 4-
substituents.42 In these new studies, we investigated not only
additional 2- and 4-substituents, but also 6- and 7-substituents,
the two regions that have not been previously explored for
SETD8.
We rst explored the 4-amino moiety of the quinazoline
scaffold. Compounds 1–15 (Scheme 1 and Table 1) were
synthesized from commercially available 2,4-dichloro-6,7-
dimethoxyquinazoline and corresponding amines in good
yields. As previously reported,6 we displaced the 4-chloro group
with the rst set of amines at room temperature. The 2-chloro
group was substituted by the second set of amines under
microwave heating conditions, yielding the desired 2,4-dia-
mino-6,7-dimethoxyquinazolines (Scheme 1).
The ring size of the terminal cyclic amino group did not have
a signicant impact on SETD8 potency (Table 1). Pyrrolidine
(compound 1), piperidine (compound 2), and azepane
(compound 3) resulted in similar potencies. The replacement of
the cyclic amino group with an acyclic amino group such as the
dimethyl amine group (compound 4) did not lead to a signi-
cant potency change either. However, increasing the length of
the side chain from 5 to 6 carbons (compound 4 versus
compound 5) resulted in a decrease in potency. We previously
reported that decreasing the length of the side chain also led to
a decrease in potency.42 Interestingly, replacing the dimethyl
amine group with the primary amino group slightly decreased
the potency (compound 5 versus compound 6). We next explored
various conformation-constrained analogs and found that these
compounds (7–10) were not as potent as compound 1. In
addition to exploring the length of the side chain, we also
attempted to replace the straight 5-carbon chain with several
amide-containing linkers and found that amide 11 was signif-
icantly less potent than compound 1 and amide 12 was
completely inactive. We previously reported that compound 13
was weakly active against SETD8.42 Consistent with the results
of amide 12, amides 14 and 15 did not display any activity
against SETD8. Taken together, these results suggest that: (1)
the terminal pyrrolidine group can be modied without potency
loss and (2) the 5-carbon linker is optimal. In addition, we
previously demonstrated that the basicity of the pyrrolidine
nitrogen was important for maintaining potency for SETD8.42
We next investigated various 2-substituents at the quinazo-
line core (Scheme 2 and Table 2). Synthesis of compounds 16–
18 was described previously.42 Compounds 20–25 were prepared
according to the synthesis route illustrated in Scheme 1.
Buchwald–Hartwig amination reaction conditions43 were used
to synthesize compounds 19 and 26–32 from the known inter-
mediate 2-chloro-6,7-dimethoxy-N-(5-(pyrrolidin-1-yl)pentyl)quina-
zolin-4-amine42 and commercially available amines (Scheme 2).
Compounds 19 and 26–32 could not be generated using stan-
dard nucleophilic conditions (Scheme 1) in good yields. A
Suzuki coupling reaction44 was used to prepare compounds 33–
36 from the same intermediate and commercially available
aromatic boronic acids (Scheme 2).
As shown in Table 2, replacing the pyrrolidine (compound 1)
with either piperidine (compound 16) or azepane (compound
17) resulted in a signicant loss of potency, suggesting that a
larger group is disfavored. On the other hand, the replacement
of the pyrrolidine (compound 1) with the dimethyl amine group
(compound 18) did not lead to a signicant potency change.
These results were reported previously.42 Interestingly, the 3,3-
diuoroazetidine (compound 19) resulted in a large loss of
potency, possibly due to the increase of the compound's
polarity. We attempted to synthesize a simple azetidine analog,
but found that the target molecule was unstable and could not
be isolated. Adding a methyl substituent to the pyrrolidine
(compound 20) led to about two-fold drop in potency. We
previously reported that compound 21 displayed some activity
for SETD8.42 Based on this result, we attempted to introduce a
pyrrolidine with a 2–5-carbon linker and were disappointed to
nd that these compounds (22–25) did not exhibit any activity
for SETD8. We also explored unsubstituted and substituted N-
methylanilines and anilines. As shown in Table 2, unsub-
stituted N-methylaniline (compound 26) and N-methylaniline
with either an electron-donating group (methoxy, compound
27) or an electron-withdrawing group (nitro, compound 28) at
the para-position were inactive. Similarly, unsubstituted aniline
(compound 29) and anilines with either an electron-donating
group (compound 30) or an electron-withdrawing group
(compounds 31 and 32) at the para-position did not display
any activity. Finally, we attempted to replace the pyrrolidine
with a phenyl or substituted phenyl group containing an
Fig. 2 The four highlighted regions were explored for studying the
SAR of the UNC0379 series.
This journal is © The Royal Society of Chemistry 2014
Med. Chem. Commun., 2014, 5, 1892–1898 | 1893

View Article Online
MedChemComm
Concise Article
Table 1 SAR of the 4-amino moiety
Table 1 (Contd.)
R1 group
SETD8 IC50a (mM)
Compound
R1 group
SETD8 IC50a (mM)
7.3 Æ 1.0b
Compound
1
15
>250
2
7.9 Æ 0.8b
a
b
IC50 determination experiments were performed in duplicate. IC50
value was reported previously.42
3
4
7.9 Æ 1.2
7.9 Æ 1.4b
5
6
26 Æ 5
40 Æ 1
7
8
40 Æ 6
43 Æ 5
Scheme 2 Synthesis of compounds 19 and 26–36. Reagents and
conditions: (a) amines, Pd(OAc)2, (+)-BINAP, Cs2CO3, THF, microwave,
heat; (b) aromatic boronic acid, Pd(PPh3)4, K2CO3, dioxane–water,
microwave, heat. Ar, aromatic ring.
9
>250
>250
electron-donating or an electron-withdrawing group at the para-
position, but found that none of these compounds (33–36) were
active against SETD8. Taken together, these results suggest that
the SAR at the 2-substituent is very tight. The vast majority of
the modications we made led to a signicant or complete loss
of potency for SETD8.
10
11
63 Æ 19
We also extensively explored the 6- and 7-substituents
(Scheme 3 and Table 3), which were not studied previously.
Compounds 37–45 were prepared from different 6,7-substituted
2,4-dichloroquinazolines (synthesis of these intermediates is
detailed in the ESI‡) according to the synthesis route illustrated
in Scheme 1. Synthesis of compounds 46–49 is outlined in
Scheme 3. Briey, debenzylation of compound 45 via hydroge-
nation produced compound 46. Nucleophilic substitution
reactions between phenol 46 and various alkyl bromides affor-
ded compounds 47–50.
12
13
>250
32 Æ 8b
14
>250
We found that the removal of both methoxy groups
(compound 37) or the 6-methoxy group (compound 38)
completely abolished activity (Table 3). Interestingly, the
removal of the 7-methoxy group (compound 39) led to about 7-
1894 | Med. Chem. Commun., 2014, 5, 1892–1898
This journal is © The Royal Society of Chemistry 2014

View Article Online
Concise Article
MedChemComm
Table 2 SAR of the 2-substituted group
Table 2 (Contd.)
R2 group
SETD8 IC50a (mM)
Compound
R2 group
SETD8 IC50a (mM)
7.3 Æ 1.0b
Compound
1
28
>250
16
94 Æ 18b
29
30
31
32
>250
>250
>250
>250
17
18
19
>250b
9.2 Æ 1.2b
110 Æ 4
20
21
15 Æ 3
37 Æ 9b
33
34
>250
>250
22
23
24
25
>250
>250
>250
>250
35
>250
36
>250
a
b
IC50 determination experiments were performed in duplicate. IC50
value was reported previously.42
26
27
>250
>250
fold loss in potency, but it retained some activity against SETD8.
These results suggest that the 6-methoxy group may be more
important for maintaining SETD8 potency compared with the 7-
methoxy group.
We next investigated several 6-substituents while holding the
7-methoxy group constant and found that the replacement of
This journal is © The Royal Society of Chemistry 2014
Med. Chem. Commun., 2014, 5, 1892–1898 | 1895

View Article Online
MedChemComm
Concise Article
signicantly change the potency. On the other hand, the larger
7-isopropoxy group (compound 44) and the 7-benzyloxy group
(compound 45) led to more than 6-fold and 17-fold potency
drops, respectively. Interestingly, the 7-hydroxy group
(compound 46) completely abolished activity against SETD8.
We next studied whether a linear chain could be tolerated at the
7-position. We were pleased to nd that compound 47, which
contains the 7-methoxyethyloxy group, was as potent as
compound 1. However, the 7-methoxypropoxy group
(compound 48) and the 7-hydroxypropoxy group (compound 49)
Scheme 3 Synthesis of compounds 46–49. Reagents and conditions:
(a) H2, Pd/C, EtOH, room temperature; (b) RBr, K2CO3, DMF, room
temperature.
led to
a signicant decrease in potency. Interestingly,
compound 50, which contains the 7-formylaminoethyloxy
group, retained the same potency as compounds 1 and 47.
Taken together, these results suggest that the 7-position is
amenable to modications and there may be an opportunity to
create more potent inhibitors of SETD8 by further exploring this
region.
Table 3 SAR of the 6- and 7-substituted groups
Conclusions
We comprehensively studied the SAR of the quinazoline scaf-
fold represented by UNC0379 (compound 1), which was recently
discovered as the rst substrate-competitive inhibitor of SETD8.
We found a number of interesting SAR trends. They include: (1)
at the 4-position, the terminal pyrrolidine group can be modi-
ed without potency loss and the 5-carbon linker is optimal; (2)
at the 2-position, modications are generally not tolerated and
pyrrolidine and dimethylamino groups are optimal; (3) at the 6-
position, the methoxy and ethoxy groups are preferred and a
larger group or a less electron-donating group is disfavored; and
(4) at the 7-position, modications can be well tolerated and
further exploration of this region may result in more potent
SETD8 inhibitors. These SAR studies also led to the discovery of
several novel compounds (3, 40, 43, 47 and 50), which exhibited
similar potencies as compound 1. During the revision of this
paper, several novel inhibitors of SETD8 have been reported.45
Compound
R3 group
R4 group
SETD8 IC50a (mM)
1
MeO–
H–
H–
MeO–
H–
MeO–
H–
MeO–
MeO–
MeO–
EtO–
i-PrO–
BnO–
HO–
7.3 Æ 1.0b
>250
>250
52 Æ 11
9.5 Æ 0.9
61 Æ 12
46 Æ 11
11 Æ 1
48 Æ 10
130 Æ 44
>250
37
38
39
40
41
42
43
44
45
46
MeO–
EtO–
i-PrO–
Cl–
MeO–
MeO–
MeO–
MeO–
47
48
49
MeO–
MeO–
MeO–
8.0 Æ 0.8
40 Æ 12
24 Æ 3
Acknowledgements
The research described here was supported by the grant
R01GM103893 from the U.S. National Institute of General
Medical Sciences of the National Institutes of Health. The
50
MeO–
8.7 Æ 0.4
Structural Genomics Consortium is
a registered charity
(number 1097737) that receives funds from the Canada Foun-
dation for Innovation, Eli Lilly Canada, GlaxoSmithKline, the
Ontario Ministry of Economic Development and Innovation, the
Novartis Research Foundation, Pzer, AbbVie, Takeda, Janssen,
Boehringer Ingelheim, Bayer and the Wellcome Trust.
a
b
IC50 determination experiments were performed in duplicate. IC50
value was reported previously.42
the 6-methoxy group with the 6-ethoxy group did not result in a
signicant change in potency (compound 1 versus compound
40). On the other hand, the 6-isopropoxy group (compound 41)
and the 6-chloro group (compound 42) led to about 8-fold and 6-
fold loss in potency, respectively, suggesting that a larger group
or a less electron-donating group is disfavored at this position.
Lastly, we explored various 7-substituents while holding the
6-methoxy group constant. Slightly increasing the size of the 7-
methoxy group to the 7-ethoxy group (compound 43) did not
References
1 R. A. Copeland, M. E. Solomon and V. M. Richon, Nat. Rev.
Drug Discovery, 2009, 8, 724–732.
2 C. H. Arrowsmith, C. Bountra, P. V. Fish, K. Lee and
M. Schapira, Nat. Rev. Drug Discovery, 2012, 11, 384–400.
3 K. Helin and D. Dhanak, Nature, 2013, 502, 480–488.
4 S. G. Clarke, Trends Biochem. Sci., 2013, 38, 243–252.
1896 | Med. Chem. Commun., 2014, 5, 1892–1898
This journal is © The Royal Society of Chemistry 2014

View Article Online
Concise Article
MedChemComm
5 S. Kubicek, R. J. O'Sullivan, E. M. August, E. R. Hickey, 17 S. K. Verma, X. Tian, L. V. LaFrance, C. Duquenne,
Q. Zhang, M. L. Teodoro, S. Rea, K. Mechtler,
J. A. Kowalski, C. A. Homon, T. A. Kelly and T. Jenuwein,
Mol. Cell, 2007, 25, 473–481.
D. P. Suarez, K. A. Newlander, S. P. Romeril, J. L. Burgess,
S. W. Grant, J. A. Brackley, A. P. Graves, D. A. Scherzer,
A. Shu, C. Thompson, H. M. Ott, G. S. V. Aller,
C. A. Machutta, E. Diaz, Y. Jiang, N. W. Johnson,
S. D. Knight, R. G. Kruger, M. T. McCabe, D. Dhanak,
P. J. Tummino, C. L. Creasy and W. H. Miller, ACS Med.
Chem. Lett., 2012, 3, 1091–1096.
6 F. Liu, X. Chen, A. Allali-Hassani, A. M. Quinn, G. A. Wasney,
A. Dong, D. Barsyte, I. Kozieradzki, G. Senisterra, I. Chau,
A. Siarheyeva, D. B. Kireev, A. Jadhav, J. M. Herold,
S. V. Frye, C. H. Arrowsmith, P. J. Brown, A. Simeonov,
M. Vedadi and J. Jin, J. Med. Chem., 2009, 52, 7950–7953.
7 Y. Chang, T. Ganesh, J. R. Horton, A. Spannhoff, J. Liu,
A. Sun, X. Zhang, M. T. Bedford, Y. Shinkai, J. P. Snyder
and X. Cheng, J. Mol. Biol., 2010, 400, 1–7.
´˜
18 W. Zheng, G. Ibanez, H. Wu, G. Blum, H. Zeng, A. Dong,
F. Li, T. Hajian, A. Allali-Hassani, M. F. Amaya,
A. Siarheyeva, W. Yu, P. J. Brown, M. Schapira, M. Vedadi,
J. Min and M. Luo, J. Am. Chem. Soc., 2012, 134, 18004–
18014.
8 F. Liu, X. Chen, A. Allali-Hassani, A. M. Quinn, T. J. Wigle,
G. A. Wasney, A. Dong, G. Senisterra, I. Chau, 19 W. Qi, H. Chan, L. Teng, L. Li, S. Chuai, R. Zhang, J. Zeng,
A. Siarheyeva, J. L. Norris, D. B. Kireev, A. Jadhav,
J. M. Herold, W. P. Janzen, C. H. Arrowsmith, S. V. Frye,
P. J. Brown, A. Simeonov, M. Vedadi and J. Jin, J. Med.
Chem., 2010, 53, 5844–5857.
M. Li, H. Fan, Y. Lin, J. Gu, O. Ardayo, J.-H. Zhang,
X. Yan, J. Fang, Y. Mi, M. Zhang, T. Zhou, G. Feng,
Z. Chen, G. Li, T. Yang, K. Zhao, X. Liu, Z. Yu, C. X. Lu,
P. Atadja and E. Li, Proc. Natl. Acad. Sci. U. S. A., 2012, 109,
21360–21365.
9 M. Vedadi, D. Barsyte-Lovejoy, F. Liu, S. Rival-Gervier, A. Allali-
Hassani, V. Labrie, T. J. Wigle, P. A. DiMaggio, G. A. Wasney, 20 W. Yu, E. J. Chory, A. K. Wernimont, W. Tempel, A. Scopton,
A. Siarheyeva, A. Dong, W. Tempel, S.-C. Wang, X. Chen,
I. Chau, T. Mangano, X.-P. Huang, C. D. Simpson,
S. G. Pattenden, J. L. Norris, D. B. Kireev, A. Tripathy,
A. Edwards, B. L. Roth, W. P. Janzen, B. A. Garcia,
A. Petronis, J. Ellis, P. J. Brown, S. V. Frye, C. H. Arrowsmith
and J. Jin, Nat. Chem. Biol., 2011, 7, 566–574.
A. Federation, J. J. Marineau, J. Qi, D. Barsyte-Lovejoy, J. Yi,
R. Marcellus, R. E. Iacob, J. R. Engen, C. Griffin, A. Aman,
E. Wienholds, F. Li, J. Pineda, G. Estiu, T. Shatseva,
T. Hajian, R. Al-awar, J. E. Dick, M. Vedadi, P. J. Brown,
C. H. Arrowsmith, J. E. Bradner and M. Schapira, Nat.
Commun., 2012, 3, 1288.
10 F. Liu, D. Barsyte-Lovejoy, A. Allali-Hassani, Y. He, 21 D. E. Williams, D. S. Dalisay, F. Li, J. Amphlett, W. Maneerat,
J. M. Herold, X. Chen, C. M. Yates, S. V. Frye, P. J. Brown,
J. Huang, M. Vedadi, C. H. Arrowsmith and J. Jin, J. Med.
Chem., 2011, 54, 6139–6150.
M. A. Chavez, Y. A. Wang, T. Matainaho, W. Yu, P. J. Brown,
C. H. Arrowsmith, M. Vedadi and R. J. Andersen, Org. Lett.,
2013, 15, 414–417.
11 A. D. Ferguson, N. A. Larsen, T. Howard, H. Pollard, I. Green, 22 J. L. Anglin, L. Deng, Y. Yao, G. Cai, Z. Liu, H. Jiang,
C. Grande, T. Cheung, R. Garcia-Arenas, S. Cowen, J. Wu,
R. Godin, H. Chen and N. Keen, Structure, 2011, 19, 1262–1273.
G. Cheng, P. Chen, S. Dong and Y. Song, J. Med. Chem.,
2012, 55, 8066–8074.
12 S. R. Daigle, E. J. Olhava, C. A. Therkelsen, C. R. Majer, 23 K. D. Konze, A. Ma, F. Li, D. Barsyte-Lovejoy, T. Parton,
C. J. Sneeringer, J. Song, L. D. Johnston, M. P. Scott,
J. J. Smith, Y. Xiao, L. Jin, K. W. Kuntz, R. Chesworth,
M. P. Moyer, K. M. Bernt, J. C. Tseng, A. L. Kung,
S. A. Armstrong, R. A. Copeland, V. M. Richon and
R. M. Pollock, Cancer Cell, 2011, 20, 53–65.
C. J. Macnevin, F. Liu, C. Gao, X. P. Huang, E. Kuznetsova,
M. Rougie, A. Jiang, S. G. Pattenden, J. L. Norris,
L. I. James, B. L. Roth, P. J. Brown, S. V. Frye,
C. H. Arrowsmith, K. M. Hahn, G. G. Wang, M. Vedadi and
J. Jin, ACS Chem. Biol., 2013, 8, 1324–1334.
13 Y. Yao, P. Chen, J. Diao, G. Cheng, L. Deng, J. L. Anglin, 24 S. K. Knutson, N. M. Warholic, T. J. Wigle, C. R. Klaus,
B. V. V. Prasad and Y. Song, J. Am. Chem. Soc., 2011, 133,
16746–16749.
C. J. Allain, A. Raimondi, M. Porter Scott, R. Chesworth,
M. P. Moyer, R. A. Copeland, V. M. Richon, R. M. Pollock,
K. W. Kuntz and H. Keilhack, Proc. Natl. Acad. Sci. U. S. A.,
2013, 110, 7922–7927.
14 Y. Yuan, Q. Wang, J. Paulk, S. Kubicek, M. M. Kemp,
D. J. Adams, A. F. Shamji, B. K. Wagner and
S. L. Schreiber, ACS Chem. Biol., 2012, 7, 1152–1157.
15 S. K. Knutson, T. J. Wigle, N. M. Warholic, C. J. Sneeringer,
C. J. Allain, C. R. Klaus, J. D. Sacks, A. Raimondi,
C. R. Majer, J. Song, M. P. Scott, L. Jin, J. J. Smith,
E. J. Olhava, R. Chesworth, M. P. Moyer, V. M. Richon,
R. A. Copeland, H. Keilhack, R. M. Pollock and
K. W. Kuntz, Nat. Chem. Biol., 2012, 8, 890–896.
25 W. Beguelin, R. Popovic, M. Teater, Y. Jiang, K. L. Bunting,
M. Rosen, H. Shen, S. N. Yang, L. Wang, T. Ezponda,
E. Martinez-Garcia, H. Zhang, Y. Zheng, S. K. Verma,
M. T. McCabe, H. M. Ott, G. S. Van Aller, R. G. Kruger,
Y. Liu, C. F. McHugh, D. W. Scott, Y. R. Chung,
N. Kelleher, R. Shaknovich, C. L. Creasy, R. D. Gascoyne,
K. K. Wong, L. Cerchietti, R. L. Levine, O. Abdel-Wahab,
J. D. Licht, O. Elemento and A. M. Melnick, Cancer Cell,
2013, 23, 677–692.
16 M. T. McCabe, H. M. Ott, G. Ganji, S. Korenchuk,
C. Thompson, G. S. Van Aller, Y. Liu, A. P. Graves, A. D. Iii,
E. Diaz, L. V. Lafrance, M. Mellinger, C. Duquenne, 26 F. Liu, D. Barsyte-Lovejoy, F. Li, Y. Xiong, V. Korboukh,
X. Tian, R. G. Kruger, C. F. McHugh, M. Brandt,
W. H. Miller, D. Dhanak, S. K. Verma, P. J. Tummino and
C. L. Creasy, Nature, 2012, 492, 108–112.
X. P. Huang, A. Allali-Hassani, W. P. Janzen, B. L. Roth,
S. V. Frye, C. H. Arrowsmith, P. J. Brown, M. Vedadi and
J. Jin, J. Med. Chem., 2013, 56, 8931–8942.
This journal is © The Royal Society of Chemistry 2014
Med. Chem. Commun., 2014, 5, 1892–1898 | 1897

View Article Online
MedChemComm
Concise Article
27 R. F. Sweis, M. Pliushchev, P. J. Brown, J. Guo, F. L. Li, 35 J. M. Yost, I. Korboukh, F. Liu, C. Gao and J. Jin, Curr. Chem.
D. Maag, A. M. Petros, N. B. Soni, C. Tse, M. Vedadi, Genomics, 2011, 5, 72–84.
M. R. Michaelides, G. G. Chiang and W. N. Pappano, ACS 36 K. Nishioka, J. C. Rice, K. Sarma, H. Erdjument-Bromage,
Med. Chem. Lett., 2014, 5, 205–209.
28 S. Garapaty-Rao, C. Nasveschuk, A. Gagnon, E. Y. Chan,
P. Sandy, J. Busby, S. Balasubramanian, R. Campbell,
J. Werner, Y. Wang, S. Chuikov, P. Valenzuela, P. Tempst,
R. Steward, J. T. Lis, C. D. Allis and D. Reinberg, Mol. Cell,
2002, 9, 1201–1213.
F. Zhao, L. Bergeron, J. E. Audia, B. K. Albrecht, 37 J. Fang, Q. Feng, C. S. Ketel, H. Wang, R. Cao, L. Xia,
J. C. Harmange, R. Cummings and P. Trojer, Chem. Biol.,
2013, 20, 1329–1339.
H. Erdjument-Bromage, P. Tempst, J. A. Simon and
Y. Zhang, Curr. Biol., 2002, 12, 1086–1099.
29 S. R. Daigle, E. J. Olhava, C. A. Therkelsen, 38 D. B. Beck, H. Oda, S. S. Shen and D. Reinberg, Genes Dev.,
A. Basavapathruni, L. Jin, P. A. Boriack-Sjodin, C. J. Allain, 2012, 26, 325–337.
C. R. Klaus, A. Raimondi, M. P. Scott, N. J. Waters, 39 F. Yang, L. Sun, Q. Li, X. Han, L. Lei, H. Zhang and Y. Shang,
R. Chesworth, M. P. Moyer, R. A. Copeland, V. M. Richon
and R. M. Pollock, Blood, 2013, 122, 1017–1025.
30 C. G. Nasveschuk, A. Gagnon, S. Garapaty-Rao,
S. Balasubramanian, R. Campbell, C. Lee, F. Zhao,
EMBO J., 2012, 31, 110–123.
40 X. Shi, I. Kachirskaia, H. Yamaguchi, L. E. West, H. Wen,
E. W. Wang, S. Dutta, E. Appella and O. Gozani, Mol. Cell,
2007, 27, 636–646.
L. Bergeron, R. Cummings, P. Trojer, J. E. Audia, 41 M. Takawa, H.-S. Cho, S. Hayami, G. Toyokawa, M. Kogure,
B. K. Albrecht and J.-C. P. Harmange, ACS Med. Chem.
Lett., 2014, 5, 378–383.
31 Y. He, I. Korboukh, J. Jin and J. Huang, Acta Biochim. Biophys.
Sin., 2012, 44, 70–79.
Y. Yamane, Y. Iwai, K. Maejima, K. Ueda, A. Masuda,
N. Dohmae, H. I. Field, T. Tsunoda, T. Kobayashi,
T. Akasu, M. Sugiyama, S.-i. Ohnuma, Y. Atomi,
B. A. J. Ponder, Y. Nakamura and R. Hamamoto, Cancer
Res., 2012, 72, 3217–3227.
32 M. T. Bedford and S. Richard, Mol. Cell, 2005, 18, 263–272.
33 A. Siarheyeva, G. Senisterra, A. Allali-Hassani, A. Dong, 42 A. Ma, W. Yu, F. Li, R. M. Bleich, J. M. Herold, K. V. Butler,
E. Dobrovetsky, G. A. Wasney, I. Chau, R. Marcellus,
T. Hajian, F. Liu, I. Korboukh, D. Smil, Y. Bolshan, J. Min,
H. Wu, H. Zeng, P. Loppnau, G. Poda, C. Griffin, A. Aman,
J. L. Norris, V. Korboukh, A. Tripathy, W. P. Janzen,
C. H. Arrowsmith, S. V. Frye, M. Vedadi, P. J. Brown and
J. Jin, J. Med. Chem., 2014, 57, 6822–6833.
P. J. Brown, J. Jin, R. Al-awar, C. H. Arrowsmith, 43 J. P. Wolfe and S. L. Buchwald, Org. Synth., 2004, 10, 423–
M. Schapira and M. Vedadi, Structure, 2012, 20, 1425–1435. 430.
34 F. Liu, F. Li, A. Ma, E. Dobrovetsky, A. Dong, C. Gao, 44 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457–2483.
´˜
I. Korboukh, J. Liu, D. Smil, P. J. Brown, S. V. Frye, 45 G. Blum, G. Ibanez, X. Rao, D. Shum, C. Radu, H. Djaballah,
C. H. Arrowsmith, M. Schapira, M. Vedadi and J. Jin, J.
Med. Chem., 2013, 56, 2110–2124.
J. C. Rice and M. Luo, ACS Chem. Biol., 2014, DOI: 10.1021/
cb500515r.
1898 | Med. Chem. Commun., 2014, 5, 1892–1898
This journal is © The Royal Society of Chemistry 2014