Identification of a new series of STAT3 inhibitors by virtual screening

Article abstract of DOI:10.1021/ml1000273

The signal transducer and activator of transcription 3 (STAT3) is considered to be an attractive therapeutic target for oncology drug development. We identified a N-[2-(1,3,4-oxadiazolyl)]-4-quinolinecarboxamide derivative, STX-0119, as a novel STAT3 dimerization inhibitor by a virtual screen using a customized version of the DOCK4 program with the crystal structure of STAT3. In addition, we used in vitro cell-based assays such as the luciferase reporter gene assay and the fluorescence resonance energy transfer-based STAT3 dimerization assay. STX-0119 selectively abrogated the DNA binding activity of STAT3 and suppressed the expression of STAT3-regulated oncoproteins such as c-myc and survivin in cancer cells. In contrast, a truncated inactive analogue, STX-0872, did not exhibit those activities. Oral administration of STX-0119 effectively abrogated the growth of human lymphoma cells in a SCC-3 subcutaneous xenograft model without visible toxicity. Structure-activity relationships of STX-0119 derivatives were investigated using the docking model of the STAT3-SH2 domain/STX-0119.

Full text of DOI:10.1021/ml1000273

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Identification of a New Series of STAT3 Inhibitors by
Virtual Screening
Kenji Matsuno,† Yoshiaki Masuda,†,‡ Yutaka Uehara,† Hiroshi Sato,† Ayumu Muroya,‡
Osamu Takahashi,‡ Takane Yokotagawa,‡ Toshio Furuya,‡ Tadashi Okawara,§
Masami Otsuka, Naohisa Ogo,^ Tadashi Ashizawa,# Chie Oshita,# Sachiko Tai,#
Hidee Ishii,# Yasuto Akiyama,# and Akira Asai*,†
†Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku,
Shizuoka, 422-8526, Japan, ‡PharmaDesign, Inc., 2-19-8 Hatchobori, Chuo-ku, Tokyo, 104-0032, Japan, §Kumamoto Health
Science University, 325 Izumimachi, Kumamoto, 861-5598, Japan, Faculty of Medical and Pharmaceutical Sciences,
Kumamoto University, 5-1 Oe-honmachi, Kumamoto, 862-0973, Japan, ^Shizuoka Institute of Environment and Hygiene,
4-27-2 Kita-ando, Aoi-ku, Shizuoka, 420-8637, Japan, and #Shizuoka Cancer Center Research Institute, 1007 Shimo-nagakubo,
Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
ABSTRACT The signal transducer and activator of transcription 3 (STAT3) is
considered to be an attractive therapeutic target for oncology drug development.
We identified a N-[2-(1,3,4-oxadiazolyl)]-4-quinolinecarboxamide derivative, STX-
0119, as a novel STAT3 dimerization inhibitor by a virtual screen using a customized
version of the DOCK4 program with the crystal structure of STAT3. In addition, we
used in vitro cell-based assays such as the luciferase reporter gene assay and the
fluorescence resonance energy transfer-based STAT3 dimerization assay. STX-0119
selectively abrogated the DNA binding activity of STAT3 and suppressed the
expression of STAT3-regulated oncoproteins such as c-myc and survivin in cancer
cells. In contrast, a truncated inactive analogue, STX-0872, did not exhibit those
activities. Oral administration of STX-0119 effectively abrogated the growth of
human lymphoma cells in a SCC-3 subcutaneous xenograft model without visible
toxicity. Structure-activity relationships of STX-0119 derivatives were investigated
using the docking model of the STAT3-SH2 domain/STX-0119.
KEYWORDS STAT3, dimerization, inhibitor, virtual screening, protein-protein
interaction, antitumor
he signal transducers and activators of transcription
(STATs) are a class of transcription factor proteins that
regulate cell growth and survival by modulating the
transcription factors, cell cycle regulators, survival proteins,
and inducers of angiogenesis.6 In addition, aberrant consti-
tutive STAT3 activation is observed in a broad spectrum of
solid and hematopoietic tumors.
T
expression of specific target genes. They are activated by various
extracellular signaling proteins such as cytokines (e.g., IL-6) or
growth factors. Upon activation of cytokine receptors or growth
factor receptors, STATs are recruited and phosphorylated at a
tyrosine residue adjacent to the SH2 domain by receptor-
associated tyrosine kinases [e.g., Janus kinase (JAK)] or the
intrinsic kinase activity of growth factor receptors [e.g., platelet-
derived growth factor receptor (PDGFR)]. Once activated, phos-
phorylated STATs form homo- or heterodimers by reciprocal
phosphotyrosine-SH2 interactions [i.e., protein-protein interac-
tion (PPI)], and then, the dimers translocate to the nucleus, where
they bind to their respective DNA binding motifs within the
promoter elements of target genes and induce transcription.1,2
STATs consist of seven isoforms (STAT1-4, STAT5a,
STAT5b, and STAT6), and among these, STAT3 is considered
to be a good target for the treatment of cancer.2-5 STAT3
drives the malignant progression of tumors through dysre-
gulation of the expression of target proteins, including
Recently, several STAT3 inhibitors have been reported, and
some of these were capable of inducing apoptosis in cancer cell
lines, that is, Phaeosphaeride A,7 Cucurbitacin Q,8 CDDO-Im,9
and 4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid
ester.7,10 Most of these compounds function through inhibition
of STAT3 signaling; however, few inhibitors of STAT3 dimeriza-
tion are known (Chart S-1). Only peptide mimetics,11 STA-21,12
Stattic,13 S3I-201 (NSC74859),14 and 5,15-DPP15 have been
reported to inhibit STAT3 dimerization. Herein, we report the
identification of STX-0119 as a new class of STAT3 dimerization
inhibitors by virtual screening and in vitro assays. We also
describe the synthesis, structure-activity relationships (SARs),
Received Date: February 4, 2010
Accepted Date: July 1, 2010
Published on Web Date: July 13, 2010
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Table 1. Inhibitory Activity on STAT3 Transcription and STAT3 Dimerization
STAT3 transcriptiona
100 μM (%) IC50 (μM)
STAT3 dimerizationb
compd no.
R1
R2
X
50 μM (%)
10 μM (%)
1a (STX-0872)
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
Me
H
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
-5
43
-4
-2
c
c
1b
Cl
Ph
NT
NT
1c (STX-0119)
99
74
55
66
63
62
70
9
1d
1e
1f
1-naphthyl
2-furyl
2-thienyl
2-pyridyl
3-pyridyl
piperidino
Ph
121
129
91
14
c
c
NT
NT
56
18
c
c
1g
1h
1i
5
NT
NT
c
c
12
NT
NT
c
c
-7
14
NT
NT
c
c
1j
NT
NT
c
c
1k
1l
Et
Ph
33
NT
NT
c
c
COOEt
Ph
Ph
38
NT
NT
1m
1n
1o
1p
1q
1r
Ph
105
5
66
60
43
c
c
2-ClPh
4-ClPh
CH2Ph
3-furyl
2-thienyl
2-furyl
Ph
NT
NT
c
c
Ph
115
82
61
75
72
75
NT
NT
Ph
61
55
56
25
8
Ph
103
86
Ph
36
c
c
1s
Ph
26
NT
NT
a STAT3-dependent luciferase reporter gene assay in HeLa cells. Percent inhibition at 100 μM or IC50
.
b FRET-based STAT3 dimerization assay. Percent
inhibition at 50 and 10 μM. c Not tested.
and biological evaluations including in vivo efficacy of STX-0119
derivatives.
reporter gene assay (no inhibition at 100 μM, Table 1). To
examine the ability of STX-0119 to inhibit STAT3 dimeriza-
tion in cells, a fluorescence resonance energy transfer
(FRET) assay22 was performed. As shown in Figure 1A,
pretreatment of the cells with STX-0119 prior to IL-6 stimula-
tion resulted in the reduction of FRET signals. In addition, a
chromatin immunoprecipitation (ChIP) assay of STX-0119-
treated MDA-MB-468 cells revealed a reduction in amplifica-
tion of the c-myc promoter, which is one of the targets for
transcriptional activation by STAT3 (Figure 1C). Inhibitory
activities were not exhibited by the inactive analogue STX-
0872 in those assays. These results suggest that the DNA
binding activity of STAT3 was effectively inhibited by STX-
0119 presumably due to disruption of STAT3 dimerization in
cells. To further evaluate the effects of STX-0119 against
downstream transcriptional activation by STAT3, we inves-
tigated the expression of its target proteins in human breast
cancer MDA-MB-468 cells. Western blotting analysis of lysate
from MDA-MB-468 cells treated with STX-0119 showed that
STX-0119 reduced the expression of STAT3 target proteins,
namely, c-myc, cyclin D1, and survivin, in a concentration-
dependent manner (Figure 1C). STX-0872, however, did not
suppress the expression of those STAT3-regulated oncopro-
teins (data not shown). It is noteworthy that STX-0119 has no
effect on the level of STAT3 or Tyr705-phosphorylated STAT3
We conducted virtual screening for inhibitors of STAT3
dimerization using CONSENSUS-DOCK,16 a customized ver-
sion of the DOCK417 program, in which three scoring func-
tions (DOCK4, FlexX,18 and PMF19) and consensus scoring20
were utilized. The crystal structure of DNA-bound STAT3β
homo dimer (PDB code 1BG121) was used for the docking
study. The Ala703-Pro704-pTyr705-Leu706-Lys707-Thr708
residues in the binding region of the STAT3-SH2 domain
from which the DNA and the dimerization partner of STAT3
had been removed were determined to be the docking
region.12,14 We virtually screened approximately 3.6 ꢀ 105
molecules (2.7 ꢀ 105 compounds). After docking of the
3.6 ꢀ 105 3D molecules into the STAT3-SH2 domain using
CONCENSUS-DOCK was completed, we selected 136 com-
pounds by consensus scoring (see the Supporting Infor-
mation) and visual inspection (for detecting the compounds
that still had some hydrogen bonds or ionic interactions
following removal of the improperly strained conformers).
Then, using a STAT3-dependent luciferase reporter gene
assay (HeLa cells) of these 136 compounds purchased from
commercial sources, we identified STX-0119 as a STAT3
inhibitor (99% inhibition at 100 μM, Table 1). A truncated
analogue lacking the 2-Ph, STX-0872, was inactive in this
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Figure 1. Functional evaluation of STAT3 inhibition in cells by STX-0119 and its inactive analogue STX-0872. (A) FRET assay: Effect of
compounds on the FRETsignals generated from interactions between STAT3-CFP and STAT3-YFP in HEK293 cells. (B) ChIP assay: Effect of
compounds on the c-myc promoter binding by STAT3 in MDA-MB-468 cells. (C) Western blotting analysis: Effect of STX-0119 on Tyr705
phosphorylation of STAT3 and expression of STAT3-regulated oncoproteins in MDA-MB-468 cells.
Scheme 1. Preparation of Compound 1 Seriesa
(Figure 1B). This suggests that STX-0119 inhibits STAT3
dimerization through a direct interaction with the STAT3
protein and not via the modulation of upstream regulators
such as JAK.
We next examined the selectivity of STX-0119 against
STAT3. Nuclear lysates from MDA-MB-468 cells treated with
STX-0119 were analyzed. As shown in Figure S-1A, the DNA
binding activity of STAT3 was suppressed by STX-0119 treat-
ment. No inhibition of DNA binding activity of other STAT
family members, namely, STAT1, STAT5a, and STAT5b, was
observed. Selective induction of apoptosis against cancer
cells harboring constitutively activated STAT3 was further
examined by measuring the caspase-3/7 activity in cells
treated with STX-0119. The human breast cancer cell line
MDA-MB-468 was shown to harbor the constitutively acti-
vated pSTAT3 (Tyr705), but MDA-MB-453 did not (data not
shown). STX-0119 induced apoptosis in MDA-MB-468 cells
(Figure S-1B). However, STX-0119 had a minimal effect on
MDA-MB-453 cells. Taken together, the results suggest that
STX-0119 selectively disrupted STAT3 dimerization and the
subsequent transcriptional activity of STAT3, followed by the
induction of apoptosis of cancer cells with constitutively
active STAT3.
Next, we synthesized N-[2-(1,3,4-oxadiazolyl)]-4-quinoline-
a Reagents and conditions: (a) SOCl2, reflux. (b) Pyridine, room
temperature, then 60 ꢀC. (c) HATU, HOAt, Huenig base, DMF. (d) KSCN,
MeCN. (e) MeCN. (f) TsCl, pyridine.
carboxamide analogues (1) to explore the SARs of STX-0119.
The methods of synthesis are outlined in Scheme 1. Condensa-
tion of 2-amino-1,3,4-oxadiazole (6a) with acid halide (3),
which was prepared from the corresponding carboxylic acid
(2) and SOCl2, provided the desired compounds (method A);
however, the purification was difficult in several cases due to
the formation of various byproduct. An alternative method was
employed with condensation of carboxylic acid (2) using
HATU-HOAt providing the desired compounds (method B).
STX-0119 (1c) was also synthesized by the following procedure
to confirm the expected acylation at the exo-amino position;
bis(acyl)thiosemicarbazide (5), which was obtained from acy-
lisothiocyanate (4) and 2-furoylhydrazide, was cyclized by TsCl
in pyridine to afford STX-0119 (1c) (method C). The NMR and
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liquid chromatography-mass spectrometry spectra were in
agreement by all three methods and the originally purchased
STX-0119. Also, the synthesized STX-0119 demonstrated
similar inhibitory activity on the STAT3-dependent luciferase
reporter gene assay (data not shown). Compounds 6a and 6b
were prepared by cyclization of acylthiosemicarbazide (8) by
iodine oxidation and sulfuric acid, respectively (Scheme S-1).
Almost all of the synthesized compounds were of >95%
purity, except compound 1b with 91% purity (see the Support-
ing Information).
The inhibitory activity of the synthesized compounds
on STAT3-dependent luciferase reporter gene assay is listed
in Table 1. Among the analogues with various 2-substituents
on the quinoline ring (1a-i), 1c-f showed a similar degree
of inhibitory activity, whereas 2-H (1a) and 2-Cl (1b) were
inactive. Thus, an aromatic or bulky substituent at this posi-
tion is essential for inhibition of STAT3. Also, replacement of
the 2-phenyl group on the quinoline ring with a pyridyl (1g,h)
or piperidino (1i) group completely abolished activity, sug-
gesting that the nitrogen atom on the pyridine or piperidine
ring might have a detrimental effect on inhibitory activity.
Regarding the 5-substituent on the 1,3,4-oxadiazole ring
(1j-r), 3-furyl (1q), 2-thienyl (1r), phenyl (1m), and benzyl
(1p) groups were tolerated. The incorporation of 4-Cl (1o) in
the phenyl ring retained activity; however, the incorporation
of 2-Cl (1n) rendered the compound inactive. As analogues
with lower alkyl groups (1j,k) and COOEt (1l) were inactive,
an aromatic or bulky hydrophobic substituent is also essen-
tial at this position. In addition, 1,3,4-thiadiazole (1s) was
completely inactive. We speculated that the reason forsuch a
considerable difference in activity between 1c and 1s might
be due to the conformational difference, namely, an unique
intramolecular CdO S interaction for acylamino-1,3,4-
Figure 2. Docking model of STX-0119 with the STAT3-SH2 do-
main generated by CONSENSUS-DOCK. Visible by MOE. (A) Sur-
face of the electrostatic map. (B) Residues of STAT3. Carbon atoms
of STX-0119 are colored yellow, and those of the phosphotyrosine
peptide (Pro704-pTyr705-Leu706-Lys707-Thr708) are colored
cyan.
3 3 3
thiadiazole.23 Most of the compounds that showed inhibitory
activity in the luciferase-based reporter assay also inhibited
STAT3 dimerization in cells (Table 1).
A docking model of STX-0119 bound to the STAT3-SH2
domain was generated on the basis of the crystal structure of
the STAT3β homo dimer (PDB code 1BG121) by CONSENSUS-
DOCK. As illustrated in Figure 2, the 2-Ph ring is inserted into
the hydrophobic cleft where it comes into proximity with the
phospho-tyrosine binding pocket, providing a strong ratio-
nale for the lack of activity of analogues bearing a smaller
substituent such as H (1a) or Cl (1b) at this position. The
amide-NH participates in a hydrogen bond interaction with
the backbone amide-CdO of Ser636. In addition, a hydro-
phobic interaction around the furan ring and a CH-π inter-
action with the indole moiety of Trp623 is observed, in
accordance with the finding that inactive analogues con-
tained a lower alkyl group at this position.
Finally, we evaluated the antitumor activity of STX-0119
in vivo. We selected the human lymphoma cell line SCC-3
that had been characterized as a cell line that expresses
constitutively activated STAT3 and the most sensitive to
STX-0119 in vitro among cell lines used.24 SCC-3 was
implanted into the hind flank of male BALB/cA-ν/ν nude
mice and allowed to establish sizable tumors. Oral gavages
of STX-0119 at 160 mg/kg sid for 4 days suppressed
the growth of SCC-3 cells significantly (p < 0.05) on the
Table 2. Antitumor Activity upon Treatment with STX-0119 in the
SCC-3 Lymphoma Xenograft Model
T/C (%)
significance
body weight change (g)
þ0.3
mortality
0/5
40
p < 0.05
fourth day, as shown in Table 2. Pharmacokinetic analysis
showed that the plasma concentration of STX-0119 was
maintained at >100 μg/mL (>260 μM), even at 8 h after
administration (Supporting Information). No obvious
body weight loss or toxicological effects were observed
during the evaluation. To our knowledge, this is the first
demonstration of in vivo efficacy following oral adminis-
tration of a STAT3 dimerization inhibitor.
In this study, we have demonstrated that a combination of
virtual screening and in vitro assays is an effective approach
for the identification of PPI modulators and that STAT3
inhibitors could provide a new therapeutic approach for
cancer treatment. Further optimization of the compound 1
series is underway.
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SUPPORTING INFORMATION AVAILABLE Supplemental
data, spectroscopic data with methods of synthesis for all com-
pounds, and methods of biological evaluation. This material is
available free of charge via the Internet at http://pubs.acs.org.
McMurray, J. S. Conformationally constrained peptidomi-
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AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. E-mail: aasai@u-shizuoka-ken.ac.jp.
Funding Sources: This work was supported by a grant from the
National Institute of Biomedical Innovation, Japan (06-2).
ACKNOWLEDGMENT We thank Yasuko Watanabe, Chika
Tokuyama, and Yoshimi Ogaki for their excellent technical assistance
in chemical synthesis and biological evaluations.
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ABBREVIATIONS STAT, signal transducers and activators
of transcription; JAK, Janus kinase; PDGFR, platelet-derived
growth factor; VEGF, vascular endothelial growth factor; PPI,
protein-protein interaction; SARs, structure-activity rela-
tionships; PCA, principle components analysis; MACCS,
Molecular ACCess System; MOE, molecular operating environ-
ment; FRET, fluorescence resonance energy transfer; ChIP,
chromatin immunoprecipitation.
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