Discovery of 1,8-disubstituted-[1,2,3]triazolo[4,5-c]quinoline derivatives as a new class of Hippo signaling pathway inhibitors

Article abstract of DOI:10.1016/j.bmcl.2019.08.001

Inhibitors of the Hippo signaling pathway have been demonstrated to have a potential clinical application in cases such as tissue repair and organ regeneration. However, there is a lack of potent Hippo pathway inhibitors at present. Herein we report the discovery of a series of 1,8-disubstituted-[1,2,3]triazolo[4,5-c]quinoline derivatives as a new class of Hippo pathway inhibitors by utilizing a cell line-based screening model (A549-CTGF). Structure-activity relationship (SAR) of these compounds was also discussed. The most potent compound in the A549-CTGF cell assay, 11g, was then evaluated by real-time PCR and immunofluorescence assays. Overall, this study provides a starting point for later drug discovery targeting the Hippo signaling pathway.

Full text of DOI:10.1016/j.bmcl.2019.08.001

Journal Pre-Proof
Discovery of 1,8-Disubstituted-[1,2,3]triazolo[4,5-c]quinoline Derivatives as a
New Class of Hippo Signaling Pathway Inhibitors
Jingxin Qiao, Guifeng Lin, Anjie Xia, Zhiyu Xiang, Pei Chen, Guo Zhang, Linli
Li, Shengyong Yang
PII:
S0960-894X(19)30527-X
https://doi.org/10.1016/j.bmcl.2019.08.001
BMCL 26597
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 April 2019
11 July 2019
1 August 2019
Please cite this article as: Qiao, J., Lin, G., Xia, A., Xiang, Z., Chen, P., Zhang, G., Li, L., Yang, S., Discovery of
1,8-Disubstituted-[1,2,3]triazolo[4,5-c]quinoline Derivatives as a New Class of Hippo Signaling Pathway
Inhibitors, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.08.001
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JOURNAL PRE-PROOF
Discovery of 1,8-Disubstituted-[1,2,3]triazolo[4,5-c]quinoline Derivatives as a
New Class of Hippo Signaling Pathway Inhibitors
Jingxin Qiao a,#, Guifeng Lina,#, Anjie Xiaa,#, Zhiyu Xianga, Pei Chenb, Guo Zhanga,
Linli Lib, Shengyong Yanga,*
a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan
University, Chengdu, Sichuan 610041, China
b Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education,
West China School of Pharmacy, Sichuan University, Sichuan 610041, China
# These authors contributed to this work equally
* Corresponding author. State Key Laboratory of Biotherapy and Cancer Center, West
China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. Tel.: +86-28-
85164063; fax: +86-28-85164060. E-mail address: yangsy@scu.edu.cn
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ABSTRACT
Inhibitors of the Hippo signaling pathway have been demonstrated to have a potential
clinical application in cases such as tissue repair and organ regeneration. However,
there is a lack of potent Hippo pathway inhibitors at present. Herein we report the
discovery of a series of 1,8-disubstituted-[1,2,3]triazolo[4,5-c]quinoline derivatives as
a new class of Hippo pathway inhibitors by utilizing a cell line-based screening model
(A549-CTGF). Structure-activity relationship (SAR) of these compounds was also
discussed. The most potent compound in the A549-CTGF cell assay, 11g, was then
evaluated by real-time PCR and immunofluorescence assays. Overall, this study
provides a starting point for later drug discovery targeting the Hippo signaling pathway.
Keywords
Hippo signaling pathway, tissue repair and organ regeneration, small molecule inhibitor,
structure-activity relationship
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The Hippo pathway is an evolutionarily conserved signaling module that plays critical
roles in organ size control, tissue repair, and organ regeneration, as well as
tumorigenesis.1–5 Core components of the Hippo pathway include the mammalian
Ste20-like kinases (Mst1/2), the cofactor Salvador (Sav1), the large tumor suppressor
(Lats1/2), and two downstream effectors Yes-associated protein (YAP) and the
transcriptional co-activator with PDZ-binding motif (TAZ).6-8 It has been established
that Mst1/2 and Sav1 form a complex to phosphorylate and activate Lats1/2, and
Lats1/2 kinases in turn phosphorylate and inhibit the transcription co-activators, YAP
and TAZ.9,10 Numerous studies have shown that inactivation of the Hippo pathway
could lead YAP/TAZ (un-phosphorylated) to translocate into the nucleus and promote
transcription of pro-proliferative and pro-survival genes,9-12 hence benefiting the tissue
repair and organ regeneration,13-19 which implies a potential clinical application of
small molecule inhibitors of Hippo pathway. Discovery of small molecule inhibitors of
the Hippo pathway has thus attracted much attention in recent years.1,3,4,15
Despite great efforts, small molecule inhibitors of the Hippo pathway are still rare.
Currently, only one compound, 4-((5,10-dimethyl-6-oxo-6,10-dihydro- 5H-
pyrimido[5,4-b]thieno[3,2-e][1,4]diazepin-2-yl)amino)benzenesulfonamide (XMU-
MP-1), has been reported to be able to efficiently inhibit the Hippo pathway and
displayed ability to promote the repair and regeneration of damaged liver and
intestinal.1 To discover more new potent Hippo pathway inhibitors, we in this
investigation established a cell line-based screening model in advance, which is an
A549 cell line that stably expresses firefly luciferase driven by connective tissue growth
factor (CTGF) promoter and Renilla luciferase driven by cytomegalovirus (CMV)
promoter (called A549-CTGF cells hereafter); CTGF is a target gene of Hippo
pathway.20 As expected, XMU-MP-1 treatment increased the relative level of firefly
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luciferase in a concentration-dependent manner (Figure 1A). To further confirm the up-
regulation of CTGF expression induced by XMU-MP-1, mRNA level of endogenous
CTGF in A549-CTGF cells was detected by real-time PCR. Consistent with the dual-
luciferase reporter assays, the mRNA level of endogenous CTGF was up-regulated by
XMU-MP-1 treatment (Figure 1B). These results demonstrated the effectiveness of the
A549-CTGF screening model. We then used this model to screen our own chemical
library containing about 2000 unique compounds synthesized by our group, which
results are shown in Figure 1C. Anumber of compounds were found to be able to inhibit
the Hippo pathway. The most potent one corresponds to compound (S)-1-(1-(3-
fluorophenyl)ethyl)-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-
2,3-dihydro-1H-
[1,2,3]triazolo[4,5-c]quinoline (T111), which showed similar activity with XMU-MP-
1 in this assay. T111 was then chosen as a hit compound for further structural
optimization.
The structural optimization was focused on two regions of T111 (R1, R2; Figure
2). Various substituents were used to replace R1 and R2, and a total of 28 new
compounds were synthesized. Bioactivities of these compounds were measured by the
A549-CTGF cell assay.
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Figure 1. (A) XMU-MP-1 effectively increased relative firefly luciferase level of the
A549-CTGF cells in a concentration-dependent manner. Dual-luciferase reporter
assays of A549-CTGF cells were performed after 24 h culture in the presence of XMU-
MP-1. Data are represented as mean ±SEM of three independent experiments. The
relative firefly luciferase level of dimethyl sulfoxide (DMSO)-treated A549-CTGF
cells was arbitrarily taken as 1. (B) XMU-MP-1 was able to up-regulate endogenous
CTGF mRNA levels in A549-CTGF cells. A549-CTGF cells were treated with XMU-
MP-1 (10 μM) or DMSO (0.1%) for 24 h, and total RNA was extracted. The mRNA
level of endogenous CTGF in A549-CTGF cells was detected by real-time PCR. (C)
Screening results of about 2,000 compounds at the concentration of 10 μM by the dual-
luciferase reporter assays. The relative firefly luciferase level of DMSO-treated A549-
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CTGF cells was arbitrarily taken as 1.
Figure 2. (A) Chemical structure of T111. (B) Focuses of the structural modification.
In the first step, we changed the R1 group with different substituents and fixed R2
as the original 1H-pyrrolo[2,3-b]pyridin-5-yl group. 15 compounds (11b-n) were
synthesized. The synthetic routes for these compounds are depicted in Scheme 1.
Briefly, commercially available 2-amino-5-bromobenzoic acid (1) reacted with 2-
nitroacetaldehyde oxime to produce 2, which was dehydrated to give 3. Intermediate 4
was prepared through chlorination of 3. Various amines then reacted with 4 to deliver
5a-5n by nucleophilic substitution reactions, which were reduced to offer the
corresponding amines 6a-6n. 6a-6n went through a diazotization and condensation to
produce the triazoloquinoline compounds 7a-7n. 7-Azaindole 8a reacted with
benzenesulfonyl chloride to give N-protected intermediate 9a, which underwent
Miyaura borylation to prepare 10a. Compounds T111 and 11b-n were finally obtained
through Suzuki coupling between 7a-7n and 10a, and subsequent deprotection by
NaOH.
Scheme 1. Synthetic routes for compounds 11b-11n, and T111.
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Reagents and conditions: (i) (1) HCl, H2O, room temperature, (2) NaOH, H2O, 0 °C,
(3) HCl, H2O, 0 °C; (ii) AcOK, Ac2O, 120 °C; (iii) POCl3, reflux; (iv) substituted amine,
triethylamine, EtOH, reflux; (v) Fe, AcOH, 60 °C; (vi) NaNO2, AcOH/H2O; (vii)
benzenesulfonyl chloride, NaH, THF, 0 °C; (viii) bis(pinacolato)diboron, PdCl2(dppf),
AcOK, 1,4-dioxane, 100 °C; (ix) (1) PdCl2(dppf), K2CO3, 1,4-dioxane/H2O, 100 °C; (2)
NaOH, EtOH/H2O, reflux.
These compounds were then tested for their bioactivity on the A549-CTGF cell
model at a series of concentrations (Table 1 and S1). Because T111 contains an S
configuration meta-fluoro-substituted 1-arylethyl group at the R1 position, we first
examined the bioactivity of enantiomer 11b with an R configuration meta-fluoro-
substituted 1-arylethyl group at the R1 position. The result showed that the bioactivity
of 11b was obviously reduced compared with that of T111, indicating that the S
configuration meta-fluoro-substituted 1-arylethyl group is more favorable than the
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corresponding R configuration at the R1 position. Replacement of the meta-fluoro with
meta-methoxyl led to a decreased activity (11c). When the fluorine atom was moved to
the para-position from meta-position on the phenyl group, the bioactivity improved
remarkably (11e vs T111). We then tested the bioactivity of the unsubstituted
compound 11g, which gave a further enhanced potency. 11d, 11f and 11h displayed
weaker bioactivity than their corresponding enantiomer 11c, 11e and 11g, which
confirmed that the S configuration 1-arylethyl groups are preferred than the
corresponding R configuration moieties at the R1 position. Next, 1-phenylethyl group
was changed to 1-phenylpropyl group, and the resulted compound 11i exhibited
reduced activity (11i vs 11g). Again, R configuration 1-phenylpropyl compound 11j
displayed weaker potency compared with S configuration 11i. Finally, we replaced the
1-arylethyl group with smaller substitution groups, including 4-fluoro-benzyl (11k), 4-
fluoro-phenyl (11l), methyl (11m) and isopropyl (11n). Bioactivities of all the
generated compounds significantly reduced. In short, the most potent compound
obtained in this step corresponds to 11g, which contains a (S)-1-phenylethyl group at
the R1 position.
Table 1 Bioactivities of compounds 11b-11n and T111a
Relative level of firefly
luciferase at 10 μM
Compound
R1
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4.909±0.314
2.096±0.205
3.131±0.103
2.224±0.325
T111
11b
11c
11d
6.509±1.280
11e
4.922±0.617
13.540±0.651
8.099±0.207
8.059±0.640
3.717±0.109
11f
11g
11h
11i
11j
3.872±0.124
11k
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3.443±0.132
0.550±0.013
3.382±1.273
4.923±0.322
11l
11m
11n
XMU-MP-1
a All assays were conducted in triplicate.
In the second step, we fixed R1 as the optimal (S)-1-phenylethyl group and altered
R2 with various substituents. 14 new compounds (12-25) were synthesized. Reaction
routes for these compounds are shown in Scheme 2. Briefly, through similar reaction
routes as those for 10a in Scheme 1, intermediates 10b and 10c were readily prepared.
Target compounds 12 and 13 were obtained by Suzuki coupling of intermediate 7k with
10b and 10c and then deprotection, respectively. Suzuki coupling reactions were
conducted again between 7k and various commercially available aromatic boric acid
(or ester) to produce final products 14-25.
Scheme 2. Synthetic routes for compounds 12-25.
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Reagents and conditions: (i) commercially available aromatic boric acid (or ester),
benzenesulfonyl chloride, NaH, THF, 0 ℃; (ii) bis(pinacolato)diboron, PdCl2(dppf),
AcOK, 1,4-dioxane, 100 ℃; (iii) (1) PdCl2(dppf), K2CO3, 1,4-dioxane/H2O, 100 °C;
(2) NaOH, EtOH/H2O, reflux. (iv) PdCl2(dppf), K2CO3, 1,4-dioxane/H2O, 100 °C
Table 2 shows the bioactivities of compounds 12-25. From Table 2, we can see
that the change of linking position of 1H-pyrrolo[2,3-b]pyridyl group with the scaffold
[1,2,3]triazolo[4,5-c]quinoline led to significantly decreased bioactivity (12, 13 vs
11g). Replacement of the 1H-pyrrolo[2,3-b]pyridin-5-yl group with 5-indolyl also
resulted in decreased bioactivity (14). We then replaced the R2 position with various
monocyclic groups, including substituted pyridyl (15-21), pyrimidyl (22) and phenyl
(23-25). All the resulted compounds except 15 showed significantly decreased
bioactivity or no activity; 15 showed a high bioactivity but still did not exceed 11g in
terms of the potency.
Table 2 Bioactivities of compounds 12-25a
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Relative level of firefly
luciferase at 10 μM
Compound
12
R1
0.549±0.0347
1.111±0.144
4.598±0.124
9.087±1.300
1.187±0.111
1.060±0.101
1.939±0.167
1.238±0.071
0.996±0.0154
13
14
15
16
17
18
19
20
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2.012±0.253
3.486±0.510
2.242±0.090
1.728±0.066
1.428±0.092
4.923±0.322
21
22
23
24
25
XMU-MP-1
a All assays were conducted in triplicate.
Overall, through the above structural optimization and SAR studies, we obtained
a number of new Hippo signaling pathway inhibitors containing the scaffold
[1,2,3]triazolo[4,5-c]quinoline. Among them, 11g is the most potent one. Further
bioactivity evaluation and mechanism studies were then carried out on this compound.
Firstly, we tested the effect of different concentrations of 11g on the Hippo
signaling pathway with the A549-CTGF cells. The results showed that 11g dose-
dependently increased the relative level of firefly luciferase (Figure 3A). Real-time
PCR assays were then adopted to examine the influence of 11g on the expression of
target genes CTGF and cysteine rich angiogenic inducer 61 (Cyr61) of the Hippo
signaling pathway.20 As shown in Figure 3B and 3C, the mRNA levels of CTGF and
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Cyr61 genes were up-regulated in a dose-dependent manner. Immunofluorescence
assays were also used to test the inpact of 11g on the location of the effector protein
YAP. The results showed that 11g (10 μM) led to nuclear translocation of YAP in A549-
CTGF cells (Figure 3D). The positive control XMU-MP-1 also showed the same effect
but relatively weaker.
Figure 3. (A) 11g dose-dependently increased relative firefly luciferase level in A549-
CTGF cells. After treatment with 11g for 24 h, A549-CTGF cells were subjected to
dual-luciferase reporter assays. Data are represented as mean ± SEM of three
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independent experiments. The relative firefly luciferase level of DMSO-treated A549-
CTGF cells was arbitrarily taken as 1. (B-C) 11g significantly increased mRNA levels
of endogenous CTGF (B) and Cyr61 (C) in A549-CTGF cells. A549-CTGF cells were
treated with 11g, XMU-MP-1 (XM, 10 μM) or DMSO (0.1%) for 24 h, and total RNA
was extracted. The mRNAlevels of endogenous CTGF and Cyr61 of A549-CTGF cells
were detected by real-time PCR. Data (mean ±SEM, n=4) were analyzed by Student’s
t-test. ***: P <0.001; **: P <0.01; *: P <0.05. (D) 11g promoted YAP nuclear
translocation in A549-CTGF cells. A549-CTGF cells were fixed, penetrated, incubated
with YAP antibodies and DAPI after treatment with 11g (10 μM), XMU-MP-1(10 μM)
or DMSO (0.1%) for 8 h. YAP antibodies were used to probe YAP, and DAPI was
applied for nuclear staining. Scale bar: 10 μm.
Then, a preliminary mechanism study was carried out on 11g. To this end, we first
tested the bioactivity of 11g against the kinases MST1/2 through kinase profiling
services provided by Eurofins. Unexpectedly, 11g did not show activity against these
kinases (Figure 4A). We then transferred to test the kinases LATS by KINOMEscan
provided by DiscoverX (the Eurofins kinase profiling services do not include the
kinases LATS). Again, 11g did not display activity in this assay (Figure 4B). Here we
can conclude that 11g inhibits the Hippo signaling pathway through a mechanism
different from that of XMU-MP-1, whose targets are MST1/2. To speculate potential
targets of 11g, we tested the inhibitory activity of 11g against the other kinases (422
kinases) in the whole kinase panel of Eurofins through kinase profiling service (Table
S2). In these assays, 11g showed activity against about 118 kinases (an inhibitory rate >
50% at 10 μM). Determining kinases whose inhibitions are responsible for the Hippo
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pathway suppression needs a lot of work to do, which is still underway in our group
and will be reported in near future.
Figure 4. (A) 11g showed no inhibitory activity against MST1 and MST2 in kinase
profiling services provided by Eurofins. The data are the mean ±SEM of 2 replicates.
(B) Kd values of 11g on LATS1/2 were greater than 10 μM in the KINOMEscan assay
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provided by DiscoverX. The amount of kinase measured by qPCR (Signal; y-axis) is
plotted against the corresponding concentration of 11g in log10 scale (x-axis).
In summary, we in this investigation obtained a new potent Hippo pathway
inhibitor (11g) by utilizing a cell line-based phenotype screening strategy and SAR
analyses. This compound showed higher potency than XMU-MP-1 in the CTGF dual-
luciferase reporter system, real-time PCR and immunofluorescence assays in vitro.
Nevertheless, the detailed targets of 11g and mechanism of action are still unknown,
which need further investigation.
ACKNOWLEDGEMENTS
This work was supported by the National Natural Science Foundation of China
(81573349, 81773633, and 21772130), National Science and Technology Major Project
(2018ZX09711002-014-002, 2018ZX09711002-011-019, 2018ZX09201018, and
2018ZX09711003-003-006), and 1.3.5 project for disciplines of excellence, West China
Hospital, Sichuan University.
CONFLICTS OF INTEREST
The authors declare no conflicts of interest.
Supporting Information:
Supplementary data associated with this article can be found in the online version.
REFERENCES
17

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1.
Fan F, He Z, Kong LL, et al. Pharmacological targeting of kinases MST1 and MST2 augments
tissue
repair
and
regeneration.
Sci
Transl
Med.
2016;8(352):352ra108.
doi:10.1126/scitranslmed.aaf2304
2.
3.
4.
5.
Johnson R, Halder G. The two faces of Hippo: Targeting the Hippo pathway for regenerative
medicine and cancer treatment. Nat Rev Drug Discov. 2014;13(1):63-79. doi:10.1038/nrd4161
Moya IM, Halder G. Hippo–YAP/TAZ signalling in organ regeneration and regenerative
medicine. Nat Rev Mol Cell Biol. 2019;22:211-226. doi:10.1038/s41580-018-0086-y
Leach JP, Heallen T, Zhang M, et al. Hippo pathway deficiency reverses systolic heart failure
after infarction. Nature. 2017;550(7675):260-264. doi:10.1038/nature24045
Piccolo S, Cordenonsi M, Dupont S. Molecular pathways: YAP and TAZ take center stage in
organ growth and tumorigenesis. Clin Cancer Res. 2013;19(18):4925-4930. doi:10.1158/1078-
0432.CCR-12-3172
6.
Hong W, Guan KL. The YAP and TAZ transcription co-activators: Key downstream effectors of
the mammalian Hippo pathway. Semin Cell Dev Biol. 2012;23(7):785-793.
doi:10.1016/j.semcdb.2012.05.004
7.
8.
9.
Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer.
2013;13(4):246-257. doi:10.1038/nrc3458
Dupont S, Morsut L, Aragona M, et al. Role of YAP/TAZ in mechanotransduction. Nature.
2011;474(7350):179-184. doi:10.1038/nature10137
Zhao B, Wei X, Li W, et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved
in cell contact inhibition and tissue growth control. Genes Dev. 2007;21(21):2747-2761.
doi:10.1101/gad.1602907.Hpo/Sav
10.
11.
12.
Hao Y, Chun A, Cheung K, Rashidi B, Yang X. Tumor suppressor LATS1 is a negative regulator
of oncogene YAP. J Biol Chem. 2008;283(9):5496-5509. doi:10.1074/jbc.M709037200
Totaro A, Panciera T, Piccolo S. YAP/TAZ upstream signals and downstream responses. Nat
Cell Biol. 2018;20(8):888-899. doi:10.1038/s41556-018-0142-z
Zhang J, Ji J-Y, Yu M, et al. YAP-dependent induction of amphiregulin identifies a non-cell-
autonomous component of the Hippo pathway. Nat Cell Biol. 2009;11:1444.
doi:10.1038/ncb1993.
13.
14.
Johnson RL, Martin JF. Hippo Pathway Inhibits Wnt Signaling to Restrain Cardiomyocyte
Proliferation and Heart Size. Science. 2011;6028(332):458-461. doi:10.1126/science.1199010
Grijalva JL, Huizenga M, Mueller K, et al. Dynamic alterations in Hippo signaling pathway and
YAP activation during liver regeneration. Am J Physiol Liver Physiol. 2014;307(2):G196-G204.
doi:10.1152/ajpgi.00077.2014
15.
16.
Lu L, Finegold MJ, Johnson RL. Hippo pathway coactivators Yap and Taz are required to
coordinate mammalian liver regeneration.
doi:10.1038/emm.2017.205
Exp
Mol Med. 2018;50(1):e423.
Wang J, Liu S, Heallen T, Martin JF. The Hippo pathway in the heart: pivotal roles in
development, disease, and regeneration. Nat Rev Cardiol. 2018;15(11):672-684.
doi:10.1038/s41569-018-0063-3
17.
18.
Mani K, MBBS, Diwan A, MD. Drugging the Hippo (Pathway). JACC Basic to Transl Sci.
2018;3(5):654-656. doi:10.1016/j.jacbts.2018.09.003
Liu S, Martin JF. The regulation and function of the Hippo pathway in heart regeneration. Wiley
Interdiscip Rev Dev Biol. 2019;8:e335. doi:10.1002/wdev.335
18

JOURNAL PRE-PROOF
19.
20.
Liu Y, Yang F, Li J, et al. Mesenchymal stem cells enhance liver regeneration via improving
lipid accumulation and Hippo signaling. Stem Cells Int. 2018;2018:1-11.
doi:10.1155/2018/7652359
Lai D, Ho KC, Hao Y, Yang X. Taxol resistance in breast cancer cells is mediated by the hippo
pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF. Cancer
Res. 2011;71(7):2728-2738. doi:10.1158/0008-5472.CAN-10-2711
19