Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models

Article abstract of DOI:10.1021/acsmedchemlett.7b00220

Histone lysine demethylases (KDMs) play a vital role in the regulation of chromatin-related processes. Herein, we describe our discovery of a series of potent KDM4 inhibitors that are both cell permeable and antiproliferative in cancer models. The modulat

Full text of DOI:10.1021/acsmedchemlett.7b00220

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Letter
Design of KDM4 Inhibitors with Anti-Proliferative Effects in Cancer Models
Young K. Chen, Tiziana Bonaldi, Alessandro Cuomo, Joselyn R. Del Rosario, David J.
Hosfield, Toufike Kanouni, Shih-chu Kao, Chon Lai, Neethan A. Lobo, Jennifer Matuszkiewicz,
Andrew McGeehan, Shawn M. O'Connell, Lihong Shi, Jeffrey A. Stafford, Ryan K.
Stansfield, James M. Veal, Michael S. Weiss, Natalie Y. Yuen, and Michael B Wallace
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00220 • Publication Date (Web): 27 Jul 2017
Downloaded from http://pubs.acs.org on July 28, 2017
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Design of KDM4 Inhibitors with Anti-Proliferative Effects in
Cancer Models
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Young K. Chen,† Tiziana Bonaldi,# Alessandro Cuomo,# Joselyn R. Del Rosario,† David J. Hosfield,ϕ
Toufike Kanouni,† Shihꢀchu Kao,‡● Chon Lai,† Neethan A. Lobo,‡ Jennifer Matuszkiewicz,† Andrew
McGeehan,‡ Shawn M. O’Connell,†▲ Lihong Shi,† Jeffrey A. Stafford,†■ Ryan K. Stansfield,†■ James
M. Veal,†■ Michael S. Weiss,‡□ Natalie Y. Yuen,‡ and Michael B. Wallace†*
†Celgene Quanticel Research, 10300 Campus Point Drive, Suite 100, San Diego, CA, 92121
‡Celgene Quanticel Research, 1500 Owens Street, Suite 500, San Francisco, CA, 94158
#Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milano, Italy
ϕ Ben May Department for Cancer Research, University of Chicago, 929 E. 57th St., Chicago, IL, 60637
KEYWORDS: Epigenetics, histone demethylase, KDM4, JMJD2, synthesis, cancer.
ABSTRACT: Histone lysine demethylases (KDMs) play a vital role in the regulation of chromatinꢀrelated processes. Herein we
describe our discovery of a series of potent KDM4 inhibitors that are both cell permeable and antiꢀproliferative in cancer models.
The modulation of histone H3K9me3 and H3K36me3 upon compound treatment was verified by homogeneous timeꢀresolved fluoꢀ
rescence assay and by mass spectroscopy detection. Optimization of the series using structureꢀbased drug design led to compound 6
(QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models.
The epigenetic alteration of histones by reversible methylaꢀ
tion of histone lysine residues constitutes a key mechanism of
gene activation and silencing. The complementary activities of
lysine methyl transferases (KMTs) and lysine demethylases
(KDMs) maintain homeostasis in healthy cells. However,
dysregulation and overexpression of KMTs or KDMs are
hallmarks of a number of pathologies, including cancers.1,2 As
a result, these targets have generated interest as therapeutic
targets in oncology. While advances have been made in the
area of KMT inhibitors and lysine demethylase 1 (LSD1, or
KDM1a) inhibitors,3,4 few inhibitors of the Jumonji family of
histone demethylases have been reported that show potent
cellular antiꢀproliferative effects.5 Currently there are no
known clinical trials for inhibitors of Jumonji KDMs.
including esophageal and breast cancers.15 KDM4A is associꢀ
ated with specific copy number gain of 1q12ꢀq21, a region
linked to chemotherapy resistance in ovarian cancer and mulꢀ
tiple myeloma.12,14 KDM4 genes and proteins are overexꢀ
pressed in numerous tumor types including breast, colorectal,
pancreatic, lymphoma, and gastric cancers.16ꢀ19 KDM4 family
members also play an important role in the epigenetic regulaꢀ
tion of embryonic stem cell identity.20ꢀ21
Due to its highly polar 2ꢀOG binding pocket, the Jumonji
histone demethylase class of protein presents considerable
challenges for smallꢀmolecule drug discovery. Several inhibiꢀ
tor leads have been reported which contain a carboxylic acid
functionality, but they have little or no cellular activity.22ꢀ24 To
address this liability, strategies involving bioisosteres in place
of carboxylic acids have been utilized.25 Proꢀdrug approaches,
which can add complexity to the drug development process,
have also been employed.26 Despite the inherent challenges,
drugs containing carboxylic acids are among the most successꢀ
fully marketed drugs.27 Furthermore, carboxylic acid 2ꢀOG
binding site inhibitors are currently being advanced for prolylꢀ
hydroxylase domain containing protein 2 (PHD2).28 We felt
that developable carboxylic acid inhibitors could be discovꢀ
ered for the KDM4 family as well, as long as certain physioꢀ
chemical property principles were taken into account. A
measured approach balancing the polarity of the carboxylic
acid functionality with lipophilicity and judicious placement
of a limited number of heteroatoms could yield inhibitors with
good drugꢀlikeness.25 Herein, we report our discovery of cell
permeable, selective KDM4 small molecule inhibitors that
The Jumonji KDM4 family are siteꢀspecific Nꢀmethyl lysine
demethylases which function enzymatically by way of an iron
and 2ꢀoxoglutarate (2ꢀOG) dependent oxygenase mechanism.
The KDM4 family members catalyze the demethylation of
histoneꢀ3ꢀlysineꢀ9
trimethyl
and
dimethyl
(H3K9me3/H3K9me2), which is a process linked to transcripꢀ
tional activation.6ꢀ8 Additionally, KDM4AꢀC catalyze the
demethylation of histoneꢀ3ꢀlysineꢀ36 trimethyl and dimethyl
(H3K36me3/H3K36me2), which is associated with gene reꢀ
pression, aberrant initiation, and the prevention of transcripꢀ
tional elongation.7ꢀ9 KDM4 family members have been impliꢀ
cated in events that may contribute to cancer development,
such as cellꢀcycle progression,10,11 hypoxia,11ꢀ13 and transient
siteꢀspecific copy gain.14
KDM4C has been implicated as a driver gene within the
9p23ꢀ24 amplicon, which is amplified in multiple tumor types,
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demonstrates potent onꢀtarget antiꢀproliferative effects in canꢀ 1a), which retained the enzymatic inhibitory properties in the
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cer cell models.
lead (KDM4C IC50 = 6 nM) while improving antiꢀproliferative
effects in the KYSEꢀ150 Cell BrdU assay (EC50 = 830 nM).
Compound 3 was coꢀcrystallized with KDM4A and refined to
2.5 Å resolution (Figure 1b). Consistent with other reported
KDM4 structures,29,30 the pyridinecarboxylate core binds to
the Jumonji C domain and mimics the key 2ꢀOG interactions.
The pyridine nitrogen forms a single dative bond with the Ni
(Fe surrogate) metal, while the pyridyl ring piꢀstacks with
F185 and the carboxylic acid forms important hydrogen bond
interactions with Y132 and K206. The tetrahydronaphthalene
ring system extends into the pocket formed by residues N86,
I71, Q73, Y132, A134, D135, and Y177, with the phenyl ring
of the tetrahydronaphthalene proximal to K241. The CꢀC bond
angles of the structure refined with both enantiomers are conꢀ
sistent with the assignment of compound 3 as the Rꢀ
enantiomer. The tetrahydronaphthalene 6ꢀposition methoxy
group is directed towards the backbone of H240, with space
available for further substitution.
Our efforts towards discovery of a KDM4 inhibitor began
with a screen of a subset of fragments related to pyridineꢀ2,4ꢀ
dicarboxylic acid, a wellꢀknown 2ꢀOG mimetic and pan KDM
inhibitor (KDM4C IC50 = 19 nM) that has been coꢀcrystallized
in KDM4A.29 Although less potent than 2,4ꢀPDCA at inhibitꢀ
ing KDM4C enzymatic activity, we considered the fragment
lead 3ꢀ(methylamino)isonicotinic acid 1 to be a more attractive
starting point for lead optimization. Compound 1 exhibits
promising enzymatic potency (KDM4C IC50 = 1400 nM)
while containing just a single coordinative interaction to the
Fe(II) cofactor rather than the bidentate chelator functionality
of 2,4ꢀPDCA. In addition, the 3ꢀamino functionality provides
an internal hydrogen bond with the 4ꢀposition carboxylate that
could impart improved physical properties (Chart 1). Finally,
1 also provides a handle for further substitution at a favorable
vector for SAR exploration, based on the expected binding
mode. 3ꢀAminoisonicotinic acid inhibitors have been reported,
with some compounds demonstrating modest cellular effects
(GSK, Chart 1).30
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O
OH
3
Compound
H
N
KDM4C IC50 = 6 nM
KYSE-150 EC50 = 830 nM
N
O
Chart 1. 2,4-Pyridine Carboxylic Acid, Compound 1, and
GSK Inhibitor
HO
O
HO
O
HO
O
S
H
H
N
N
OH
N
N
N
O
1
2,4-PDCA
GSK Inhibitor
IC50 = 1400 nM
KDM4C IC50 = 19 nM
From exploration of substitutions off of the 3ꢀ
aminoisonicotinic acid nitrogen, we identified the tetrahyꢀ
dronaphthalene compound 2 (Chart 2) as a potent inhibitor of
KDM4C (IC50 = 12 nM). KDM4C was originally cloned from
the esophageal cell line KYSEꢀ150,28 and shRNA knockdown
of KDM4C in KYSEꢀ150 has been shown to impair cell proꢀ
liferation.6 Therefore, we chose to utilize the same KYSEꢀ150
line for a cellꢀbased antiꢀproliferation assay measuring incorꢀ
poration of BrdU. Tested as its racemate, compound 2
demonstrated measurable inhibition of cell proliferation (EC50
= 6 µM) in the KYSEꢀ150 cell line. Given this result, the enꢀ
antiopure compounds 2a and 2b were prepared. The Rꢀ
enantiomer 2a was determined to be the active enantiomer
(KDM4C IC50 = 8 nM, KYSEꢀ150 cell EC50 = 4 µM), while
the Sꢀenantiomer 2b was shown to be relatively inactive
(KDM4C IC50 > 2 µM, KYSEꢀ150 cell EC50 > 100 µM).
Figure 1. Coꢀcrystal structure of compound 3 in the KDM4A
active site. PDB code 5VMP
.
In order to assess cellular onꢀtarget engagement of the comꢀ
pounds, we examined histone postꢀtranslational modification
patterns of inhibitorꢀtreated cells by mass spectrometry (MS)
analysis. KYSEꢀ150 cells were treated with compound 3 at
both 2 µM for 24 hours, and 300 nM for 96 hours. Untreated
and treated cells were harvested and histones purified using a
standard strongꢀacidic extraction protocol from fractionated
nuclei.31,32 Purified histone octamers were then subjected to inꢀ
gel chemical alkylation with D6ꢀacetic anhydride, followed by
trypsin digestion.33,34 The resulting histone peptide fragments
were subjected to high resolution UHPLCꢀMSMS analysis.
Three histone residues of interest—H3K4, H3K9 and H3K36
in their various methylation states (me1/me2/me3)—were
examined. MaxQuant software was used to assign peptide
sequences and identify modified sites from the MS raw data
and relative quantitation of each differentially modified hisꢀ
tone peptide was calculated as peptide relative abundance perꢀ
centage (RA%) using an intensityꢀbased approach (see Supꢀ
plemental).
Chart 2. Tetrahydronaphthalene Lead 2 and Enantiomers
HO
O
HO
O
HO
O
H
H
H
N
N
N
N
N
N
2
2b
2a
KDM4C IC50 = 12 nM
IC50 > 2000 nM
IC50 = 8 nM
KYSE-150 EC50 = 6 µM
EC50 > 100 µM
EC50 = 4 µM
Molecular modelling of compound 2a suggested that the 6ꢀ
position of the tetrahydronaphthalene ring would be optimal
for further elaboration and SAR development. Substitution
with a 6ꢀposition methoxy group gave compound 3 (Figure
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using a lentiviral transfection (KYSEꢀ150+KDM4C). Consistent
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with the mechanism of KDM4 demethylase activity, a deꢀ
crease in H3K9me3 and H3K36me3 levels was observed with
the engineered overexpression of KDM4C as compared to the
nonꢀtransfected KYSEꢀ150 (Supplementary Figure 1). The
dynamic range of the changes for H3K36me3 were more proꢀ
nounced than that for H3K9me3, and thus more amenable to
an accurate readꢀout without baseline interference. Furtherꢀ
more, we viewed the consistency afforded by the stably transꢀ
fected cell line to be more fitting for a MOA assay to guide
SAR development. The KYSEꢀ150+KDM4C mutant was treated
with inhibitor 3 at various test concentrations, and H3K36me3
was measured at 24 hours in a HTRF® assay. A doseꢀ
responsive increase in H3K36me3 was clearly demonstrated
with an EC50 value of 560 nM, a value similar in magnitude
with its antiꢀproliferative effects. In contrast, the negative
control compound 2b demonstrated no observable H3K36me3
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induction
.
Using the structural information from compound 3, we deꢀ
signed the derivatives 4—6 (Table 1) to impart favorable hyꢀ
drophobic interactions and improve cellular permeability. In
addition, we surveyed heteroatom linkers to determine the
optimal vector off of the tetrahydronaphthalene 6ꢀposition.
We were pleased to discover that compounds 4—6 displayed
potent KDM4C enzymatic activity, with the H3K36me3 MOA
tracking with antiꢀproliferative effects. Compound 6 (also
known as QC6352) showed the most promising cellular potenꢀ
cy (KYSEꢀ150 EC50 = 3.5 nM, H3K36 MOA = 1.5 nM). The
compounds were also inactive in a normal fibroblast cell line
(IMRꢀ90), demonstrating that they are not general cytotoxic
agents.
Figure 2. MS intensityꢀbased quantitation of H3 modified pepꢀ
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tides (9ꢀ17) and (27ꢀ40) from KYSEꢀ150 cells treated with comꢀ
pound 3. Percent Relative Abundances (%RAs) were calculated
for all differentially modified forms of peptides (9ꢀ17) and (27ꢀ
40) (top and bottom, respectively). A significant increase (p<0.01
twoꢀsample tꢀtest) was detected for both K9me3 and K36me3 at
24 or 96 hours of treatment, relative to the corresponding %RAs
of untreated (NT) cells. Error bars represent the standard error of
the mean from 5 technical replicates (Supplementary Table 2).
Under our enzymatic assay conditions, compounds with
high lipophilicity tended to plateau at around 40 nM. This
could be attributed in part to the limitations of the enzymatic
assay for compounds with high plasma protein binding. In
fact, the enzymatic potency of compound 6 (human PPB =
99.9%) improved from 35 nM to 9 nM when the enzymatic
assay was run with a lower BSA concentration (0.02 mg/mL
instead of 0.2 mg/mL BSA). This apparent rightꢀshift in bioꢀ
chemical activity of lipophilic compounds containing carboxꢀ
ylic acids has been documented.36 The cell permeability of the
compounds could also be a factor impacting their cellular poꢀ
tency, as the permeability measured by PAMPA improved
from compound 3 to compounds 5 and 6. Compound 6 was
enzymatically potent across the KDM4 family, and highly
selective against other KDM family members, with the excepꢀ
tion of KDM5B (Table 2). Although the inhibitor is 7 to 20ꢀ
fold more potent for KDM4s, the KDM5B activity remains
significant (IC50 = 750 nM). Therefore, we are unable to rule
out the possibility of some KDM5 family contribution to the
observed phenotype.
As displayed in Figure 2, the effects of treatment were more
pronounced at the 24ꢀhour time point, using the higher inhibiꢀ
tor concentration treatment. At this time point, treated KYSEꢀ
150 cells exhibited an increase in both H3K9me3 (>2ꢀfold)
and H3K36me3 (>6ꢀfold). Changes in the H3K4me2/me3
methylation states were below the detectable limits (see Supꢀ
plemental Table 2 for the annotation of RA% for each modiꢀ
fied peptide and the corresponding statistical analysis). An inꢀ
depth analysis of peptide H3(27ꢀ40) revealed that K27me3 is
also upꢀregulated at 24 and 96 hours relative to untreated cells.
This finding could be explained either by an indirect, adaptive
effect of the cell to compound 3 treatment, or by the recent
evidence suggesting that H3K27me3 is a novel KDM4 subꢀ
strate.35
To confirm our MS results, we developed a cellꢀbased MOA
assay to measure relevant histone methyl mark changes.
KYSEꢀ150 cells were engineered to overexpress KDM4C
Table 1. KDM4C Inhibition, KYSE-150 and IMR-90 Cell Viability, H3K36me3 Mechanism of Action (MOA) Increase, cLogD, and
PAMPA Permeability for Compound 3—6.
R
KDM4C
IC50 (nM)
KYSEꢀ150
EC50 (nM)
H3K36me3
MOA EC50
(nM)
IMRꢀ90 EC50
cLogD
PAMPA
permeability
(nm/s)
(nM)
3
4
5
6
OMe
6 ± 2
830 ± 150
150 ± 10
99 ±16
560 ± 200
>30,000
>30,000
>30,000
>30,000
0.27
1.93
2.61
2.09
18.42
OPh
17 ± 9
48 ±7
35 ± 8
32 ± 12
19 ± 5
32.25
51.50
51.18
SPh
N(Me)Ph
3.5 ± 1
1.3 ±0.3
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Table 2. Enzymatic data for compound 6 (QC6352) for KDM4
1
2
3
family isoforms, along with selectivity data for other KDM family
members. Data are derived from duplicate data points, and IC50
values are reported as the mean of multiple experiments ± s.e.m.
4
5
6
7
8
9
KDM
Compound 6
IC50 (nM)
>4,000
>4,000a
>4,000a
104 ± 10
56 ± 6
KDM
Compound 6
IC50 (nM)
35 ± 8
KDM2B
KDM3A
KDM3B
KDM4A
KDM4B
KDM4C
KDM4D
KDM5B
KDM6B
PHF8
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104 ± 18
750 ±170
>4,000
>4,000a
Figure 3. Coꢀcrystal structure of compound 6 (QC6352) in the
KDM4A active site. PDB code 5VGI
aValues derived from biochemical assay without preꢀincubation.
.
The synthesis of the lead compound 6 is described and deꢀ
picted in Scheme 1. Cyanation of 6ꢀbromochromanone 7 folꢀ
lowed by acidic hydrolysis yielded the amide intermediate 8.
Subsequent asymmetric reduction was carried out in the presꢀ
ence of Ru(OAc)2[Sꢀbinap] to give the Rꢀenantiomer 9 in high
enantiomeric excess (> 96% ee).37 Borane reduction of the
amide gave the amine 10. A chemoꢀselective Buchwaldꢀ
Hartwig crossꢀcoupling of the amine with methyl 3ꢀbromoꢀ
isonicotinate proceeded to give intermediate 11 in moderate
yield. A second BuchwaldꢀHartwig coupling of compound 11
with methyl 3ꢀbromoꢀisonicotinate followed by saponification
gave the final carboxylic acid inhibitor 6.
With an intent to understand the activity of these KDM4 inꢀ
hibitors in more pharmacologically relevant models, we tested
compound 6 in 3D organotypic cell cultures (“organoids”),
which were derived from breast and colon primary patient
samples. Both inhibition of colony formation and inhibition of
cell viability were determined in BR0869f, a HER2ꢀpositive
patientꢀderived breast cancer organoid model, and in SU60, a
patientꢀderived colon cancer organoid model. Compound 6
demonstrated an IC50 of 5 nM in BR0869f after a 5ꢀday incuꢀ
bation, and an IC50 of 13 nM in the SU60 model.
The pharmacokinetic parameters of compound 6 were deꢀ
termined in female CDꢀ1 mice. After intravenous dose adminꢀ
istration (5 mg/kg), compound 6 displayed a low systemic
clearance of 6.9 mL/min/kg and a low volume of distribution
of 675 mL/kg. Compound 6 was readily absorbed after oral
administration (dose = 10 mg/kg) with an AUC of 10,400
ng/mL*hr and an oral bioavailability of 30%.
Scheme 1. Synthesis of Compound 6
a
c
b
H2N
H2N
H2N
O
O
O
Br
Br
Br
Br
10
9
7
8
O
O
HO
O
H
e, f
H
d
N
N
N
Br
N
N
6
11
aReagents and conditions: (a) TMSCN, ZnI2, toluene, 60 ºC;
H2SO4, AcOH, H2O, 105 ºC, 80%, (b) H2, Ru(OAc)2[Sꢀbinap],
THF, MeOH, 77%, > 96% ee, (c) BH3ꢀTHF, THF, 55 ºC, 79%,
(d) methyl 3ꢀbromoꢀisonicotinate, Xantphos, Pd2(dba)3, Cs2CO3,
toluene, 120 ºC, 50%, (e) Nꢀmethylꢀaniline, Xantphos, Pd2(dba)3,
Cs2CO3, toluene, 128 ºC, 79%, (f) 1N NaOH, MeOH, 89%.
The coꢀcrystal structure of compound 6 bound to KDM4A
was solved at a resolution of 2.1 Å (Figure 3). As expected,
the inhibitor makes similar interactions to compound 3 in the
2ꢀOG pocket, with the pyridyl nitrogen ligating the active site
Ni2+ ion while Y132 and K206 form key hydrogen bonds with
the carboxylic acid. The methyl group of the Nꢀmethylaniline
substituent packs against N86 and the H240 carbonyl. The
edge of the phenyl ring interacts with the R239/H240 loop,
and the phenyl group fills the cleft that extends towards the Cꢀ
terminal region loop containing the residues 309ꢀ313. The
ligand stereocenter is again unambiguous as the Rꢀenantiomer.
Figure 4. a) Mouse in vivo efficacy of compound 6 in BR0859f
xenograft model, dosed BID on a 5 on/2 off schedule. The tumor
volumes are reported as the mean of each 8ꢀanimal group ± s.e.m.
b) Compound 6 shows effects on TIC population in the BR0869f
model. Each point represents the tumor volume of a mouse that
was inoculated with dissociated cells (50, 500, or 1000 cells) from
either the BRO869f xenograft study vehicle group or the 50
mg/kg BID group. The median value is depicted with a line.
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involved in protein production and biological assay development,
Given its potent in vitro effects and suitable PK properties,
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execution, and analysis. J.R.D.R., A.M., R.K.S., and N.Y.Y. were
responsible for the in vivo studies and analysis. T.B. and A.C.
performed the histone MS study. D.J.H. and J.M.V. were involved
in the crystallography experiments and analysis.
compound 6 was progressed in vivo utilizing the BR0869f
PDX model in mice. The compound was dosed BID on a
5on/2off schedule for 22 days at three dose levels—10 mg/kg,
25 mg/kg, and 50 mg/kg. The rate of tumor growth was diꢀ
minished in a doseꢀdependent manner versus the vehicle conꢀ
trol (Figure 4a), with tumor growth inhibitions (TGIs) of 22%,
36% and 61%, respectively. The animals’ overall body
weights remained constant for each group, and the animals
appeared in good health (Supplemental Figure 3).
ACKNOWLEDGMENTS
The authors thank the following scientists for their valuable assisꢀ
tance: Sami Bahmanyar, Robert Cho, Laure Escoubet, Xiaobo Li,
Christopher C. Park, and Jianchun Xu. We thank Dongming Qian
and Viva Biotech for diffraction data collection. We also thank
Dr. Roland Schuele at the University of Freiburg for our continuꢀ
ing collaboration related to QC6352.
9
To determine the effects of KDM4 inhibition on tumor initiꢀ
ating cell (TIC) frequency in breast cancer tumors, we evaluꢀ
ated the tumorigenic potential of BR0869f xenograft cells post
treatment with compound 6 versus vehicle. At the end of dosꢀ
ing, dissociated cells (50 to 1000) from the 50 mg/kg BID
group and the vehicle control group were injected subcutaneꢀ
ously in a limiting dilution manner into NSG mice, and tumor
volumes were measured (Figure 4b). The number of cells reꢀ
quired for tumor formation was reduced in the compound 6
treated group, and the reduction in TIC frequency was greater
than 14ꢀfold.
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In summary, we have developed a novel series of potent
KDM4 inhibitors with promising selectivity from a small
fragment lead using structureꢀbased design. These inhibitors
are strongly antiꢀproliferative in KYSEꢀ150 cells and demonꢀ
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental details on all compounds and characterizing
data, in vitro biological methods, MS methods, and in vivo
methods (PDF)
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: mwallace@celgene.com
Present Addresses
● Benitec Biopharma, 3940 Trust Way, Hayward, CA 94545
▲ Pfizer Inc. Oncology R&D, Epigenetics, 10724 Science Center
Drive, San Diego, CA 92121
■ Jecure Therapeutics, Inc., 4757 Nexus Center Drive, Suite 150,
San Diego, CA 92121
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US2010/0160682
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Design of KDM4 Inhibitors with Anti-Proliferative Effects in Cancer Models
Young K. Chen,† Tiziana Bonaldi,# Alessandro Cuomo,# Joselyn R. Del Rosario,† David J. Hosfield,ϕ Toufike Kanouni,† Shihꢀchu Kao,‡
Chon Lai,† Neethan A. Lobo,‡ Jennifer Matuszkiewicz,† Andrew McGeehan,‡ Shawn M. O’Connell,† Lihong Shi,† Jeffrey A. Stafford,†
Ryan K. Stansfield,† James M. Veal,† Michael S. Weiss,‡ Natalie Y. Yuen,‡ and Michael B. Wallace†*
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