Potent Dual BET/HDAC Inhibitors for Efficient Treatment of Pancreatic Cancer

Article abstract of DOI:10.1002/ange.201915896

As one of the most aggressive and lethal human malignancies with extremely poor prognosis, there is an urgent demand of more effective therapy for the treatment of pancreatic cancer. Reported here is a new, effective therapeutic strategy and the design of small-molecule inhibitors that simultaneously target bromodomain and extra-terminal (BET) and histone deacetylase (HDAC), potentially serving as promising therapeutic agents for pancreatic cancer. A highly potent dual inhibitor (13 a) is identified to possess excellent and balanced activities against BRD4 BD1 (IC₅₀=11 nm) and HDAC1 (IC₅₀=21 nm). Notably, this compound shows higher in vitro and in vivo antitumor potency than the BET inhibitor (+)-JQ1 and the HDAC inhibitor vorinostat, either alone or and in combination, highlighting the advantages of BET/HDAC dual inhibitors for more effective treatment of pancreatic cancer.

Full text of DOI:10.1002/ange.201915896

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Titel: Highly Potent Dual BET/HDAC Inhibitors for the Efficient
Treatment of Pancreatic Cancer
Autoren: Wei Wang, Shipeng He, Guoqiang Dong, Yu Li, Shanchao
Wu, and Chunquan Sheng
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Highly Potent Dual BET/HDAC Inhibitors for the Efficient
Treatment of Pancreatic Cancer
Shipeng He,a,b,c† Guoqiang Dong, Yu Li, Shanchao Wu, Wei Wang * and Chunquan Sheng *
a†
a
a
b,d
a,e
Abstract: As one of the most aggressive and lethal human
malignancies with extremely poor prognosis, there is an urgent
demand of more effective therapy for the treatment of pancreatic
cancer. Herein we wish to report a new, effective therapeutic
strategy that small molecule inhibitors simultaneously targeting
bromodomain and extra-terminal (BET) and histone deacetylase
cellular processes, including apoptosis, cell cycle, cell growth
and differentiation, and closely associated with several human
diseases, such as cancer.[4] The bromodomain and extra-
terminal (BET) family proteins are a subfamily of bromodomain-
containing proteins (BRDs) which consist of BRD2, BRD3,
BRD4 and BRDT.[ They recognize acetylated lysine in histones
and other proteins via their tandem bromodomains (BD1 and
BD2) and regulate gene transcription.[5] Therefore, BET proteins
represent the best characterized class of epigenetic readers and
have emerged as attractive therapeutic targets for cancers.[
(+)-JQ1 (1, Figure 1) was the first potent and selective inhibitor
reported in 2010.[7] Several BET inhibitors including I-BET762,
OTX-015, CPI-0610, TEN-010, have subsequently advanced
into clinical trials for the treatment of different cancers.[ On the
other hand, histone deacetylases (HDACs) are critical epigenetic
erasers that remove acetyl groups from lysine on histones.[
They comprise 11 components grouped into 4 classes (I, IIa, IIb,
and IV) and 7 sirtuins (class III). To date, five HDAC inhibitors
5]
(
HDAC) are rationally designed as promising therapeutic agents for
pancreatic cancer. A highly potent dual inhibitor (13a) is identified to
possess excellent and balanced activities against BRD4 BD1 (IC50
1 nM) and HDAC1 (IC50 = 21 nM). Notably, this compound shows
=
6]
1
higher in vitro and in vivo antitumor potency than BET inhibitor (+)-
JQ1, HDAC inhibitor vorinostat and their combination, highlighting
the advantages of BET/HDAC dual inhibitors for the more effective
treatment of pancreatic cancer.
8]
9]
Pancreatic cancer is one of the most aggressive and lethal
human malignancies worldwide, whose incidence and mortality
has continued to rise in the recent years.[1] It has been predicted
to become the second leading cause of cancer-related death
within the next decade.[1b] Pancreatic ductal adenocarcinoma
(
(
HDACis), namely vorinostat (2, SAHA, Figure 1), romidepsin
FK228), belinostat (PXD-101), panobinostat (LBH-589) and
Chidamide have been approved for the treatment of hematologic
cancer.[10]
(
PDAC) represents the most common form (about 95%) of
[
1a]
pancreatic cancer.
Owning to the remarkable resistance to
most therapeutic strategies, pancreatic cancer is often related to
a dismal and poor prognosis, with a 5-year survival rate less
than 5%.[2] Currently, surgery is still the main treatment for
pancreatic cancer. The first and second-line chemotherapy
relies on multi-drug combination, such as FOLFIRINOX (5-
fluorouracil, leucovorin, oxaliplatin, and irinotecan) and
gemcitabine/nab-paclitaxel. Although the combinational drug
therapeutic strategy was helpful to improve the overall survival
rate, it was also associated with severe side effects and limited
living quality of patients.[3] Therefore, it is urgent to develop new
therapeutic strategies and more effective therapeutics to
overcome these intrinsic drawbacks for challenging pancreatic
cancer.
Epigenetic regulation is involved in modulation of many
[
[
a]
b]
S. He, G. Dong, Y. Li, S. Wu, Prof. C. Sheng
School of Pharmacy, Second Military Medical University
325 Guohe Road, Shanghai 200433, China
E-mail: shengcq@smmu.edu.cn
S. He, Prof. W, Wang
School of Pharmacy, East China University of Science and
Technology
130 Meilong Road, Shanghai 200237, China
E-mail: wwang@pharmacy.arizona.edu
S. He
Institute of Translational Medicine, Shanghai University
[
c]
d]
99 Shangda Road, Shanghai 200444, China
Figure 1. Rational design of BET/HDAC dual inhibitors. (A) The binding
modes of BRD4 (PBD: 3MXF) and HDAC1 (PDB: 5ICN) inhibitors. (B) Design
strategy of BET/HDAC dual inhibitors. Compound 13a effectively inhibited
BRD4 BD1 and HDAC1 and showed potent antiproliferative activity against
Capan-1 cells. The binding of compound 13a with BRD4 BD1 was validated by
ITC assay.
[
Prof. W, Wang
Department of Pharmacology and Toxicology and BIO5 Institute,
University of Arizona
Tucson, Arizona 85721, United States
Prof. C. Sheng
School of Pharmaceutical Sciences, Zhengzhou University,
Zhengzhou 450001, China
These authors contributed equally to this work
[
e]
[†
]
Supporting information for this article is given via a link at the end of
the document.
Epigenetic aberrations have been considered as key drivers
of several human diseases and play an important role in the
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Angewandte Chemie
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onset and progression of pancreatic cancer.[11] Recent evidence
demonstrated that combination of compound 1 and 2 synergized
to increase pancreatic cancer cell death and achieved better
suppression of advanced PDAC in mice.[2] Thus, developing
small molecule simultaneously inhibiting BET and HDAC may
represent a promising, more effective therapeutic strategy for
the treatment of pancreatic cancer.
(IC50 = 0.15 μM), which was more active than BET inhibitor 1
and HDAC inhibitor 2 used alone or in combination (Table 1).
To further investigate whether compound 13a exerted
antitumor activity by synergistically dual inhibition, control
compound 22a (ZBG group blocked) and (-)-13a (enantiomer of
1
1
3a) were chosen for biological evaluation. As depicted in Table
, compound 22a showed comparable BRD4 inhibitory activity to
The key pharmacophore of BET inhibitors was investigated
by the co-crystal structure of compound 1 with BRD4.[7] As
shown in Figure 1A, compound 1 revealed excellent shape
complementarity with the acetyl-lysine (KAc) binding cavity and
formed a key hydrogen bond with evolutionarily conserved
residue Asn140. Several additional interactions near the ZA
channel and WPF shelf also contributed to ligand binding. The t-
butyloxycarboryl moiety was exposed to the solvent region,
providing a feasible site for multi-targeting design. Meanwhile,
the general pharmacophores of HDAC inhibitors, such as
compounds 2 and 3 (Figure 1B), consist of a hydrophobic cap
group, a linker, and a zinc-binding group (ZBG, hydroxamic acid
or ortho-aminobenzamide). ZBG is the essential group for HDAC
inhibition by chelating with the catalytic Zn2+ ion. Inspired by
these results, pharmacophore fusion strategy would be an
effective approach to design novel inhibitors against both targets
compound 13a but was inactive towards HDAC1. While
compound (-)-13a showed comparable HDAC1 inhibitory activity
but was inactive towards BRD4. As compared with BET/HDAC
dual inhibitor 13a, both 22a and (-)-13a were >10 times less
potent in inhibition of cell growth in Capan-1 cells. Therefore,
these studies indicate that the synergistic antitumor efficacy
highlights the therapeutic advantage of BET/HDAC dual
inhibitors.
Table 1. The synergistic antitumor effect of BET/HDAC dual inhibitor 13a
HDAC1
IC50 , nM)
BRD4 BD1
(IC50 , nM)
Capan-1
(IC50 , μM)
(
Figure 1B). Thus, a series of novel BET/HDAC dual inhibitors
Compd
R2
a
b
a
(
were designed and synthesized (Table S1, Scheme S1-4,
Supporting Information).
1
3a
2a
21 ± 1.0
> 2000
11 ± 0.70
14 ± 0.70
0.15 ± 0.080
2.1 ± 0.15
Initially, ortho-aminoanilide was used as ZBG group and two
types of dual inhibitors were prepared (compounds 7a-c and 8a-
c, Table S1, Supporting Information). Unfortunately, the HDAC1
inhibitory activity was weak (compounds 7c and 8c, Table S1,
Supporting Information). Interestingly, when ortho-aminoanilide
was replaced with hydroxamic acid (compounds 9a-c and 10a-c,
Table S1, Supporting Information), enhanced activities towards
HDAC1 coupled with improved antitumor potency were
observed. For the position of the carbon chain on the phenyl
group, para-substituted derivatives were more potent than the
corresponding meta-position analogues. Then, replacement of
the phenoxy group with amidobenzyl group (compounds 11a-c,
Table S1, Supporting Information) led to a significant decrease
of antitumor potency against Capan-1 cell line. Meanwhile,
truncated analogues (compounds 12a-d, Table S1, Supporting
Information) by removing phenyl group showed improved activity
against HDAC1 but decreased potency towards BRD4.
Compounds 12c and 12d exhibited the best HDAC1 inhibitory
activities with the IC50 values of 1.1 nM and 1.2 nM, respectively.
However, these compounds only displayed moderate in vitro
antitumor potency. Finally, removal of the alkane chain afforded
compounds 13a-b. In particular, compound 13a revealed potent
and balanced inhibitory activity against both targets (BRD4 BD1
IC50 = 11 nM, HDAC1 IC50 = 21 nM). Isothermal titration
calorimetry (ITC) assay confirmed the binding affinity of
2
(
-)-13a
-
-
-
29 ± 3.1
NTa
> 2000
29 ± 7.1
NTc
3.2 ± 0.80
8.6 ± 2.1
5.4 ± 1.9
1
2
46 ± 7.0
1
+ 2
-
-
-
1.0 ± 0.20
(1:1)
aIC50 values are the mean of at least three independent experiments
performed in triplicate with standard deviation. IC50 values are the mean of at
least two independent experiments performed in duplicate with standard
deviation. cNT = Not tested.
Table 2. BET isoform profiling of compound 13a (IC50a, nM)
b
Isoform
BRD2 BD1
BRD2 BD2
BRD3 BD1
BRD3 BD2
BRD4 BD1
BRD4 BD2
BRDT BD1
BRDT BD2
BRD1
13a
316 ± 6.0
78 ± 4.0
1
929 ± 225
336 ± 104
361 ± 47
133 ± 30
38 ± 1.0
97 ± 15
11 ± 0.7
29 ± 7.1
69 ± 4.9
103 ± 17
254 ± 77
826 ± 103
767 ± 69
302 ± 83
32200 ± 500
12900 ± 500
43900 ± 8600
62400 ± 10100
42300 ± 7200
15800 ± 1300
36800 ± 4700
49800 ± 9400
EP300
SP140
SMARCA2
aIC50 values are the mean of at least two independent experiments performed
in duplicate with standard deviation.,
d
compound 13a to BRD4 BD1, with a dissociation constant (K )
of 90 nM (Figure 1B). Molecular docking study revealed the
binding mode of compound 13a with BRD4 and HDAC1 (Figure
S1, Supporting Information). Moreover, compound 13a
processed the best antitumor potency against Capan-1 cells
To explore the BET and HDAC isoform selectivity,
compound 13a was evaluated against four BET isoforms and
five HDAC isoforms (HDAC1-3, HDAC6 and HDAC8). Moreover,
four non-BET BRDs (BRD1, EP300, SP140 and SMARCA2
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Angewandte Chemie
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COMMUNICATION
belonging to the subfamily III, IV, V and VIII, respectively) were
also selected for BRDs selectivity profile investigation.[8] As
depicted in Table 2, compound 13a was a potent pan-BET
inhibitor with IC50 values ranging from 11 to 316 nM. Similarly to
compound 1, compound 13a was inactive against all the four
non-BET BRDs, demonstrating its high selectivity for BET
bromodomains. The HDAC profiling revealed that compound
effects in vivo than that of compound 1 and 2 used alone or in
combination. Notably, no significant body weight loss and no
obvious adverse effects were observed during the study (Figure
S2, Supporting Information), suggesting the low toxicity of
compound 13a. The results underscored the advantages of
BET/HDAC dual inhibitors as novel antitumor agents and
provided an efficient strategy for pancreatic cancer therapy.
1
3a was a potent pan-HDAC inhibitor with nanomolar activity
against all the tested HDAC isoforms with IC50 values ranging
from 21 to 192 nM (Table 3).
Table 3. HDAC isoform profiling of compound 13a (IC50a, nM)
Compds
HDAC1
21 ± 3.0
46 ± 7.0
HDAC2
52 ± 1.0
172 ± 6.0
HDAC3
39 ± 1.0
26 ± 5.0
HDAC6
34 ± 1.0
17 ± 1.0
HDAC8
192 ± 6.0
3379 ± 93
13a
2
aIC50 values are the mean of at least two independent experiments performed
in duplicate with standard deviation.
To explore whether compound 13a suppressed BET and
HDAC in cancer cells, the levels of c-Myc, CDC25B, acetylated
histone H3 and H4 (acetyl-H3 and acetyl-H4) were determined
by Western blotting assay. As shown in Figure 2A, compound
1
3a effectively decreased c-Myc and CDC25B levels in Capan-1
cells in a dose-dependent manner. Moreover, exposure to
compound 13a dose-dependently induced an increase of acetyl-
H3 and acetyl-H4. The results confirmed that compound 13a
inhibited both targets in Capan-1 cells. Real-time quantitative
PCR (RT-qPCR) analysis was also performed to explore the
oncogenes c-Myc and CDC25B expression. As depicted in
Figure 2B, c-Myc and CDC25B mRNA levels were significantly
suppressed by 13a in Capan-1 cells. Furthermore, we
investigated the ability of compound 13a in inducing apoptosis in
Capan-1 cells. As illustrated in Figure 2C, compound 13a
caused significant induction of apoptosis in Capan-1 cells at a
concentration of 0.5 μM and displayed a much higher apoptosis
rate (63.5%) than BET inhibitor 1 and HDAC inhibitor 2 used
alone or in combination. All these results validated the
synergistic effect of compound 13a at the cellular level.
Figure 2. Effects of compound 13a in Capan-1 cells. (A) Western blotting
analysis of c-Myc, CDC25B, acetyl-H3 and acetyl-H4 levels in Capan-1 cells
treated with test compounds. (B) Similar to (A) but examined for c-Myc and
CDC25B mRNA expression by RT-qPCR. (C) Cell apoptosis induced by
compound 13a. Capan-1 cells were incubated with DMSO and 0.5 μM of
compounds for 48 h. Apoptosis was examined by flow cytometer. At least
three biological replicates were done for each condition. Data were presented
as mean ± standard deviation. * P < 0.05, ** P < 0.01 and *** P < 0.001 vs
control group, determined with Student’s t test.
On the basis of the balanced activities against BRD4 and
HDAC1 as well as excellent in vitro antineoplastic potency,
compound 13a was progressed to the evaluation of in vivo
antitumor efficacy. Initially, the metabolic stability of compound
1
3a was evaluated with mouse liver microsomes. The results
indicated that compound 13a had acceptable metabolic stability
with a T1/2 value of 44.29 min (Table S2, Supporting Information).
Then, a Capan-1 human pancreatic cancer xenograft model was
prepared according to the procedure described previously,[12]
and compound 13a and positive controls were administered
intraperitoneally (ip). As shown in Figure 3, treatment with
compound 13a (15 mg/kg or 20 mg/kg bid ip for 21 consecutive
days) exhibited excellent antitumor effects in a dose-dependent
manner, with tumor growth inhibition (TGI) values of 69% and
Figure 3. In vivo antitumor efficacy of compound 13a in Capan-1 tumor
xenograft model. (A) Growth curve of implanted Capan-1 xenograft in nude
mice. Data are expressed as the mean ± standard error of the mean (SEM). *
P < 0.05, ** P < 0.01, vs the vehicle group, determined with Student’s t test. (B)
Picture of dissected Capan-1 tumor tissues.
To further illuminate the mechanism of compound 13a in
vivo, immunofluorescence and Western blotting assays were
used to detect the expression of related proteins in tumor tissues.
As shown in Figure 4A, the red fluorescence intensity of tumor
tissues gradually decreased in the 13a treatment group,
indicating a down-regulation of c-Myc. Quantitative real time
polymerase chain reaction (RT-qPCR) analysis was also
performed to detect c-Myc and CDC25B mRNA levels. As
8
7.7%, respectively. In contrast, ip dosing with compound 1 (15
mg/kg, bid) and 2 (15 mg/kg, bid) achieved TGI values of 41%
and 49%, respectively. Meanwhile, the combination of
compounds 1 (15 mg/kg, bid, ip) and 2 (15 mg/kg, bid, ip) was
more potent with a higher TGI value (57%). Taken together,
compound 13a demonstrated significantly better antineoplastic
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illustrated in Figure 4B, compound 13a significantly decreased
the expression of mRNA encoding c-Myc and CDC25B, which
was more effective than compounds 1, 2 and their combination.
The same result was obtained by Western blotting assay
China (grant 2017YFA0506000 to C. S.), and the Innovation
Program of Shanghai Municipal Education Commission (Grant
2019-01-07-00-07-E00073 to C.S.).
(
Figure 4C). In contrast, the expression levels of Acetyl-H3 and
Keywords: BET • HDAC • dual inhibitors • pancreatic cancer •
Acetyl-H4 were increased in tumor tissues (Figure 4C, and
Figure S3, Supporting Information), indicating the efficient
suppression of both BET and HDAC pathways in mice.
antitumor efficacy
[
1]
a) J. Kleeff, M. Korc, M. Apte, C. La Vecchia, C. D. Johnson, A. V.
Biankin, R. E. Neale, M. Tempero, D. A. Tuveson, R. H. Hruban, J. P.
Neoptolemos, Nat. Rev. Dis. Primers 2016, 2, 16022; b) L. Rahib, B. D.
Smith, R. Aizenberg, A. B. Rosenzweig, J. M. Fleshman, L. M.
Matrisian, Cancer Res. 2014, 74, 2913-2921.
[
2]
P. K. Mazur, A. Herner, S. S. Mello, M. Wirth, S. Hausmann, F. J.
Sanchez-Rivera, S. M. Lofgren, T. Kuschma, S. A. Hahn, D. Vangala,
M. Trajkovic-Arsic, A. Gupta, I. Heid, P. B. Noel, R. Braren, M. Erkan, J.
Kleeff, B. Sipos, L. C. Sayles, M. Heikenwalder, E. Hessmann, V.
Ellenrieder, I. Esposito, T. Jacks, J. E. Bradner, P. Khatri, E. A. Sweet-
Cordero, L. D. Attardi, R. M. Schmid, G. Schneider, J. Sage, J. T.
Siveke, Nat. Med. 2015, 21, 1163-1171.
[
3]
a) T. Conroy, P. Hammel, M. Hebbar, M. Ben Abdelghani, A. C. Wei, J.
L. Raoul, L. Chone, E. Francois, P. Artru, J. J. Biagi, T. Lecomte, E.
Assenat, R. Faroux, M. Ychou, J. Volet, A. Sauvanet, G. Breysacher, F.
Di Fiore, C. Cripps, P. Kavan, P. Texereau, K. Bouhier-Leporrier, F.
Khemissa-Akouz, J. L. Legoux, B. Juzyna, S. Gourgou, C. J.
O'Callaghan, C. Jouffroy-Zeller, P. Rat, D. Malka, F. Castan, J. B.
Bachet, G. Canadian Cancer Trials, G. I. P. G. the Unicancer, N. Engl.
J. Med. 2018, 379, 2395-2406; b) D. D. Von Hoff, T. Ervin, F. P. Arena,
E. G. Chiorean, J. Infante, M. Moore, T. Seay, S. A. Tjulandin, W. W.
Ma, M. N. Saleh, M. Harris, M. Reni, S. Dowden, D. Laheru, N. Bahary,
R. K. Ramanathan, J. Tabernero, M. Hidalgo, D. Goldstein, E. Van
Cutsem, X. Wei, J. Iglesias, M. F. Renschler, N. Engl. J. Med. 2013,
369, 1691-1703.
[
[
[
4]
5]
6]
C. H. Arrowsmith, C. Bountra, P. V. Fish, K. Lee, M. Schapira, Nat. Rev.
Drug Discov. 2012, 11, 384-400.
P. Filippakopoulos, S. Knapp, Nat. Rev. Drug Discov. 2014, 13, 337-
356.
V. Sahai, A. J. Redig, K. A. Collier, F. D. Eckerdt, H. G. Munshi,
Oncotarget 2016, 7, 53997-54009.
Figure 4. The immunofluorescence analysis of c-Myc (A) protein, mRNA
expression of c-Myc and CDC25B (B) and Western blotting detection of c-Myc
CDC25B and Acetyl-H3 (C) protein expression in transplanted nude mice.
Data are expressed as the mean ± standard deviation. * P < 0.05, ** P < 0.01,
[7]
P. Filippakopoulos, J. Qi, S. Picaud, Y. Shen, W. B. Smith, O. Fedorov,
E. M. Morse, T. Keates, T. T. Hickman, I. Felletar, M. Philpott, S. Munro,
M. R. McKeown, Y. Wang, A. L. Christie, N. West, M. J. Cameron, B.
Schwartz, T. D. Heightman, N. La Thangue, C. A. French, O. Wiest, A.
L. Kung, S. Knapp, J. E. Bradner, Nature 2010, 468, 1067-1073.
Z. Liu, P. Wang, H. Chen, E. A. Wold, B. Tian, A. R. Brasier, J. Zhou, J.
Med. Chem. 2017, 60, 4533-4558.
*
** P < 0.001, vs the vehicle group, determined with Student’s t test.
[
[
[
8]
9]
In summary, a series of novel BET/HDAC dual inhibitors
were designed and synthesized based on synergistic effect of
BET and HDAC inhibitors on pancreatic cancer. In particular,
compound 13a showed excellent and balanced activity against
both BRD4 and HDAC1 and demonstrated the best antitumor
potency. Importantly, compound 13a processed excellent in vivo
antitumor efficacy in Capan-1 xenograft models (TGI = 87.7%,
K. J. Falkenberg, R. W. Johnstone, Nat. Rev. Drug Discov. 2014, 13,
673-691.
10] M. Manal, M. J. Chandrasekar, J. Gomathi Priya, M. J. Nanjan, Bioorg.
Chem. 2016, 67, 18-42.
[11] a) A. L. McCleary-Wheeler, G. A. Lomberk, F. U. Weiss, G. Schneider,
M. Fabbri, T. L. Poshusta, N. J. Dusetti, S. Baumgart, J. L. Iovanna, V.
Ellenrieder, R. Urrutia, M. E. Fernandez-Zapico, Cancer Lett. 2013, 328,
2
0 mg/kg, ip, bid), which was much more potent than BET
212-221; b) S. B. Baylin, P. A. Jones, Nat. Rev. Cancer 2011, 11, 726-
inhibitor 1 and HDAC inhibitor 2 used alone or in combination.
This study highlighted the advantages of BET/HDAC dual
inhibitors as novel and promising antitumor agents and provided
an efficient strategy for the treatment of pancreatic cancer.
734.
[
12] S. He, G. Dong, S. Wu, K. Fang, Z. Miao, W. Wang, C. Sheng, J. Med.
Chem. 2018, 61, 7245-7260.
Acknowledgements
This work was supported by National Natural Science
Foundation of China (grants 21738002 to W. W., 81725020 to C.
S., and 81872742 to G. D.) the National Key R&D Program of
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Entry for the Table of Contents (Please choose one layout)
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†
†
Shipeng He, Guoqiang Dong, Yu Li,
Shanchao Wu , Wei Wang* and
Chunquan Sheng*
Page No. – Page No.
Highly Potent Dual BET/HDAC
Inhibitors for the Efficient Treatment
of Pancreatic Cancer
One stone kills two birds: The highly potent dual BET/HDAC inhibitors were uncovered to possess excellent activities in vitro and in
vivo. This proof-of-concept study demonstrates a powerful and efficient strategy for the treatment of pancreatic cancer.
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