Discovery of a Prenylated Flavonol Derivative as a Pin1 Inhibitor to Suppress Hepatocellular Carcinoma by Modulating MicroRNA Biogenesis

Article abstract of DOI:10.1002/asia.201801461

Peptidyl-prolyl cis-trans isomerase Pin1 plays a crucial role in the development of human cancers. Recently, we have disclosed that Pin1 regulates the biogenesis of miRNA, which is aberrantly expressed in HCC and promotes HCC progression, indicating the therapeutic role of Pin1 in HCC therapy. Here, 7-(benzyloxy)-3,5-dihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-en-1-yl)-4H-chromen-4-one (AF-39) was identified as a novel Pin1 inhibitor. Biochemical tests indicate that AF-39 potently inhibits Pin1 activity with an IC₅₀ values of 1.008 μm, and also displays high selectivity for Pin1 among peptidyl prolyl isomerases. Furthermore, AF-39 significantly suppresses cell proliferation of HCC cells in a dose- and time-dependent manner. Mechanistically, AF-39 regulates the subcellular distribution of XPO5 and increases miRNAs biogenesis in HCC cells. This work provides a promising lead compound for HCC treatment, highlighting the therapeutic potential of miRNA-based therapy against human cancer.

Full text of DOI:10.1002/asia.201801461

DOI: 10.1002/asia.201801461
Communication
Pin1 Inhibitors
Discovery of a Prenylated Flavonol Derivative as a Pin1 Inhibitor
to Suppress Hepatocellular Carcinoma by Modulating MicroRNA
Biogenesis
Yuanyuan Zheng+,[a] Wenchen Pu+,[a] Jiao Li+,[a] Xianyan Shen,[b] Qiang Zhou,[b] Xin Fan,[a]
Sheng-Yong Yang,[a] Yamei Yu,[a] Qiang Chen,[a] Chun Wang,[b] Xin Wu,*[a] and Yong Peng*[a]
tumor progression through activating some oncogenes (such
Abstract: Peptidyl-prolyl cis-trans isomerase Pin1 plays a
crucial role in the development of human cancers. Recent-
ly, we have disclosed that Pin1 regulates the biogenesis of
miRNA, which is aberrantly expressed in HCC and pro-
motes HCC progression, indicating the therapeutic role of
Pin1 in HCC therapy. Here, 7-(benzyloxy)-3,5-dihydroxy-2-
(4-methoxyphenyl)-8-(3-methylbut-2-en-1-yl)-4H-chromen-
4-one (AF-39) was identified as a novel Pin1 inhibitor. Bio-
chemical tests indicate that AF-39 potently inhibits Pin1
activity with an IC50 values of 1.008 mm, and also displays
high selectivity for Pin1 among peptidyl prolyl isomerases.
Furthermore, AF-39 significantly suppresses cell prolifera-
tion of HCC cells in a dose- and time-dependent manner.
Mechanistically, AF-39 regulates the subcellular distribu-
tion of XPO5 and increases miRNAs biogenesis in HCC
cells. This work provides a promising lead compound for
HCC treatment, highlighting the therapeutic potential of
miRNA-based therapy against human cancer.
as PML-RARa and c-Myc) and inactivating many tumor sup-
pressors (such as AMPK and FBXW).[4,5] Therefore, Pin1 is a po-
tential therapeutic target for cancer treatment.
Several small-molecular Pin1 inhibitors have been discov-
ered. Juglone from walnut trees, with 1,4-naphthoquinone
moiety, is the first Pin1 inhibitor and irreversibly inhibits the
enzymatic activity of Pin1.[6] The Juglone analogue KPT-6566
was reported to covalently interact with Pin1 and promote its
structural change and degradation, thus inhibiting cell prolifer-
ation.[7] Tea polyphenol EGCG was found to interfere with the
substrates recognition of Pin1 via blocking the cis-trans isomer-
ization.[8] All-trans retinoic acid (ATRA) inhibits and degrades
active Pin1 selectively in cancer cells by directly binding to the
substrate phosphate- and proline-binding pockets in the Pin1
active site.[9] Recently, 6-O-benzylguanine derivative API-1 have
been found to locate into Pin1 PPIase domain and suppress
Pin1 function in vitro and in vivo.[10] However, the study on the
small molecular Pin1 inhibitors is still in their infancy, and no
Pin1 inhibitors have been applied to clinical treatment against
solid tumors, including hepatocellular carcinoma (HCC).
HCC is one of the most common human malignancies
worldwide, with 5-year survival rate 7%.[11] Currently, sorafenib
is the only FDA-approved first-line drug for advanced HCC, but
failed to achieve a satisfactory response rate.[12,13] Numerous
evidences suggest that aberrant microRNA (miRNA) expression,
mainly attributed to impaired miRNA biogenesis, is correlated
with HCC development.[14,15] Recently, we have disclosed that
Pin1 can modulate the conformation of ERK-phosphorylated
exportin-5 (XPO5, responsible for export of precursor miRNA
(pre-miRNA) from the nucleus to the cytoplasm), interfere the
nucleus-to-cytoplasm export of pre-miRNA and downregulate
miRNA expression in HCC,[16,17] highlighting the therapeutic po-
tential of Pin1 in HCC via modulating miRNA biogenesis.
The peptidyl-prolyl cis-trans isomerase Pin1 is an unique
enzyme responsible for isomerizing the phosphorylated
Serine/Threonine-Proline (pS/T-P) motif, post-translationally
regulating the biological function of Pin1 substrates.[1,2] In
human cells, Pin1 is a key regulator of multiple physiological
processes including RNA processing and cell cycle progres-
sion.[3] Increasing evidences indicate that Pin1 is overexpressed
and/or overactivated in certain malignancies and accelerates
[a] Y. Zheng,+ Dr. W. Pu,+ Dr. J. Li,+ X. Fan, Prof. S.-Y. Yang, Prof. Y. Yu,
Prof. Q. Chen, Prof. X. Wu, Prof. Y. Peng
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital
Sichuan University and Collaborative Innovation Center of Biotherapy
Chengdu (China)
In this study, we performed computer-aided drug virtual
screening based on the crystal structure of Pin1 PPIase domain
(PDB ID: 3IKD and 3I6C) to identify Pin1 inhibitors from natural
product and natural product-like compound library (>10000
compounds), and evaluated the Pin1 inhibitory activity of hit
compounds using in vitro PPIase activity assays. Pin1 PPIase
domain is the bona fide moiety for catalyzing cis-trans isomeri-
zation of pS/T-P motif and altering the structure and function
of substrates.[18] Intriguingly, nearly all tested flavonols had
high putative PPIase affinity and exhibited significant inhibition
E-mail: wuxinsmile@sina.com
yongpeng@scu.edu.cn
[b] X. Shen, Q. Zhou, Prof. C. Wang
Chengdu Institute of Biology
Chinese Academy of Sciences
Chengdu (China)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under:
https://doi.org/10.1002/asia.201801461.
Chem. Asian J. 2018, 00, 0 – 0
1
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
against Pin1 (Table S1). Thus, we planned to investigate the po-
tential of flavonols as novel Pin1 inhibitors for HCC therapy.
First, a series of flavonol derivatives were designed and
chemically synthesized. To synthesize C-6, C-7, C-3’, C-4’ and/or
C-5’ substituted flavonols, starting from 2-hydroxy acetophe-
nones and benzaldehydes, the racemic flavanones were pre-
pared via piperidine-mediated Claisen-Schmidt condensation/
O-Michael addition tandem reaction.[19] The obtained flava-
nones were then oxidized into corresponding flavonols in the
presence of lithium hydroxide and hydrogen peroxide with
high overall yields (AF-1–AF-17, Scheme 1 and Table S2). Fur-
thermore, to prepare C-5 substituted flavonols, we conducted
Scheme 2. Synthesis of flavonols AF-18–AF-32.
With these compounds in hand, we evaluated their Pin1 in-
hibitory activity based on in vitro PPIase activity assay at 10 mm
of sample concentration. Among these tested flavonols, preny-
lated compound AF-39 had the strongest Pin1 inhibitory activ-
ity in vitro (Figure 1A). The IC50 value of AF-39 was 1.008 mm,
exhibiting improved activity than juglone (Figure 1B). AF-18,
AF-19, AF-38 were less potent than AF-39 (Figure S1). To con-
firm whether AF-39 has high selectivity for Pin1, we expressed
and purified other three peptidyl-prolyl isomerases from E. coli,
including Pin4, FKBP12 and cyclophilin A, to analyze PPIase ac-
tivity in vitro. The results indicated that AF-39 had an excellent
inhibitory activity to Pin1 rather than other PPIases at the con-
centrations of 1, 10 and 50 mm (Figure 1C), suggesting good
Pin1 selectivity of AF-39.
To check whether AF-39 interacts with Pin1 directly, we per-
formed cellular thermal shift (CETSA). As in Figure 2A, AF-39
remarkably increased the thermal stability of Pin1 protein with
a thermal shift of 1.728C, indicating the direct binding of AF-
39 and Pin1. To further investigate bind pattern of AF-39 and
Pin1, flexible molecular docking calculation was performed. As
shown in Figure 2B, flexible docking results indicated that AF-
39 was located in the Pin1 PPIase domain. AF-39 interacts
with amino acid residues Lys63 and Arg69 by s-p interaction,
and with Ser114 by hydrogen bond, providing a theoretical
basis for the selective inhibition of AF-39 against Pin1.
Scheme 1. Synthesis of flavonols AF-1–AF-17.
self-developed sodium carbonate/hydrogen peroxide-mediated
Algar-Flynn-Oyamada reaction and smoothly afforded fifteen
C-5 substituted flavonols from corresponding chalcones with
acceptable yields (AF-18–AF-32, Scheme 2 and Table S3).[20] Re-
cently, the prenylated flavonoids draw great attention due to
their attractive biological function in cells.[21] Thus, to obtain
prenylated flavonols and more natural product-like com-
pounds, eight flavonols were semi-synthesized from kaempfer-
ol step-by-step (AF-33–AF-40, Scheme 3).
Scheme 3. Synthesis of flavonols AF-33–AF-40.
&
&
Chem. Asian J. 2018, 00, 0 – 0
www.chemasianj.org
2
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
Figure 1. (A) PPIase activity assay using Pin1 as enzyme treated with flavonols (10 mm). (B) PPIase activity assay of AF-39 using Pin1 as enzyme and juglone as
positive control. (C) PPIase activity assay of AF-39 using recombination Pin1, Pin4, FKBP12 or cyclophilin A as enzymes at the sample concentration of 1, 10,
50 mm.
Figure 2. (A) Cellular thermal shift assay (CETSA) in the lysate of SK-Hep-1 cells with or without AF-39 treatment. (B) Flexible docking of AF-39 with Pin1.
To test the cellular activity, AF-39 was subjected to MTT
assay in HCC cells. As shown in Figure 3A, AF-39 significantly
suppressed cells proliferation in both SK-Hep-1 and SNU-423
cells, with the IC50 values of 3.86 and 5.698 mm, respectively.
Moreover, a dose-dependent inhibition was also observed in
SK-Hep-1 cells when the cells were treated with AF-39 for 24,
48, 72 and 96 hours (Figure 3B). This anti-cancer activity was
further confirmed by colony formation assay in SK-Hep-1 cells
treated with AF-39 (Figure 3C). Importantly, AF-39 did not
show distinct cytotoxity to normal hepatocytes (Figure S2).
These results suggested that AF-39 had anti-proliferative activi-
ty in a dose- and time-dependent manner.
Our previous study has demonstrated that Pin1 inhibits
XPO5-mediated export of pre-miRNAs from the nucleus to the
cytoplasm, thus leading to decreased miRNA expression and
promoting HCC development.[16,17] To investigate whether AF-
39 affects the subcellular distribution of XPO5, we performed
immunofluorescence by confocal microscope and immuoblot-
ting of XPO5 after nucleus-cytoplasm isolation. The results
showed that XPO5 mainly located in the nucleus of SK-Hep-1
cells, and AF-39 treatment significantly increased its cytoplas-
mic distribution, suggesting that AF-39 restored the nucleus-
to-cytoplasm export of XPO5 in HCC cells (Figure 4A and 4B).
To further verify whether AF-39 had an effect on miRNA bio-
Chem. Asian J. 2018, 00, 0 – 0
www.chemasianj.org
3
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
of miR-122 gene dramatically increased the tumour incidence
of mouse, and delivery of miR-122 to a MYC-driven mouse
model of HCC strongly inhibited tumorigenesis, supporting the
tumor suppressor activity of miR-122 and a potential miRNA-
based therapy for HCC.[24–26] MiR-29b also shows tumor sup-
pressor activity, because it was reported to reduce the War-
burg effect by inhibiting AKT pathway and also induce apopto-
sis by targeting Mcl-1.[27,28] Our study showed that AF-39 spe-
cifically interacts with the PPIase domain to inhibit Pin1 activity
and restore the nucleus-to-cytoplasm export of pXPO5, thus in-
creasing miRNA expression, such as miR-122 and miR-29b.
Therefore, the anticancer effect of AF-39 may be attributed to
its regulation of miRNA biosynthesis.
In the past few years, some flavonols and flavone analogues
were discovered as targeted inhibitors via computer-aided vir-
tual screening[29] and displayed attractive anticancer activity.
For instance, amentoflavone, a JAK2 inhibitor by structure-
based virtual screening of a natural product library, showed en-
hanced potency against oncogene JAK2.[30] In this work, we
screened out flavonol AF-39 as a novel Pin1 inhibitor, which
potently suppressed HCC cells, highlighting the potential of
flavonols in the therapy of human cancers.
Figure 3. (A) MTT assays in SK-Hep-1 and SNU-423 cells treated with the indi-
cated doses of AF-39. (B) MTT assays in SK-Hep-1 cells treated with 5, 10 and
25 mm of AF-39 for the indicated times. (C) Effect of AF-39 on colony forma-
tion assay in SK-Hep-1 cells.
In summary, the prenylated flavonol AF-39 was identified as
a novel Pin1 inhibitor. AF-39 has an effective and high specific
inhibitory effect on Pin1, suppressing HCC cells in a dose- and
time dependent manner. Mechanistic studies suggest that AF-
39 regulates the distribution of XPO5 and increase the biogen-
esis of mature miRNAs (miR-122, miR-29b). Therefore, this work
provides a promising lead compound for HCC treatment, high-
lighting miRNA-targeted therapy in human cancers.
genesis, we conducted real-time quantitative PCR to measure
miRNA expression. As expected, AF-39 obviously upregulated
the expression of miR-122 and miR-29b (Figure 4C). To test the
pXPO5 dependence of AF-39, we characterized the anti-prolif-
erative activity of AF-39 in Huh7-CTL (low XPO5 phosphoryla-
tion) and Huh7-MEKDD (high XPO5 phosphorylation) cells.[10]
As in Figure S3, the activity of AF-39 was sharply reduced
when pXPO5 was at a low level, indicating the pXPO5 depend-
ance of AF-39. Unlike ATRA[9] and KPT-6566,[7] AF-39 did not
induce Pin1 degradation (Figure S4). These results provided a
potential mechanism for the anti-cancer effect of AF-39 in HCC
cells.
Acknowledgements
This work was supported by National Natural Science Founda-
tion of China (81572739 to Y.P., 81702980 to W.P.), China Post-
doctoral Science Foundation (2017M612976 to W.P.).
MiR-122 is the most abundant and liver-specific miRNA,
whose expression is significantly downregulated in HCC.[22]
While the expression of the transcription factor c-Myc, a well-
known oncogene, is frequently up-regulated in HCC. Moreover, Conflict of interest
miR-122 and c-Myc form a double-negative feedback loop to
reciprocally regulate their expression.[23] Importantly, deletion
The authors declare no conflict of interest.
Figure 4. (A) Confocal imaging of XPO5 subcellular localization in SK-Hep-1 cells after treatment with AF-39 (2.5 mm) or DMSO. (B) Immunoblotting of XPO5,
Lamin B1 and b-actin against their corresponding antibodies in SK-Hep-1 cells with or without AF-39 treatment after nucleus-cytoplasm isolation. (C) Relative
expression of mature miRNAs detected by real-time quantitative PCR in SK-Hep-1 cells with AF-39 (2.5 mm) or DMSO incubation.
&
&
Chem. Asian J. 2018, 00, 0 – 0
www.chemasianj.org
4
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
Wang, T. Kim, N. Zanesi, Y. J. Jeon, T. J. Lee, J. H. Guh, M. C. Hung, K.
Ghoshal, C. M. Teng, Y. Peng, C. M. Croce, Cancer Cell 2016, 30, 723.
[17] J. Li, W. Pu, H. L. Sun, J. K. Zhou, X. Fan, Y. Zheng, J. He, X. Liu, Z. Xia, L.
Liu, Y. Q. Wei, Y. Peng, Cell Death Differ. 2018, 25, 1612.
Keywords: cancer · flavonol · hepatocellular carcinoma ·
microRNA · Pin1 · XPO5
[18] K. P. Lu, G. Finn, T. H. Lee, L. K. Nicholson, Nat. Chem. Biol. 2007, 3, 619.
[19] S. Bano, K. Javed, S. Ahmed, I. G. Rathish, S. Singh, M. Chaitanya, K. M.
Arunasree, M. S. Alam, Eur. J. Med. Chem. 2013, 65, 51.
[20] X. Shen, Q. Zhou, W. Xiong, W. Pu, W. Zhang, G. Zhang, C. Wang, Tetra-
hedron 2017, 73, 4822.
[21] X. Chen, E. Mukwaya, M. S. Wong, Y. Zhang, Pharm. Biol. 2014, 52, 655.
[22] W. Filipowicz, H. Grosshans, Prog. Drug Res. 2011, 67, 221.
[23] B. Wang, S. H. Hsu, X. Wang, H. Kutay, H. K. Bid, J. Yu, R. K. Ganju, S. T.
Jacob, M. Yuneva, K. Ghoshal, Hepatology 2014, 59, 555.
[24] S. H. Hsu, B. Wang, J. Kota, J. Yu, S. Costinean, H. Kutay, L. Yu, S. Bai, K.
La Perle, R. R. Chivukula, H. Mao, M. Wei, K. R. Clark, J. R. Mendell, M. A.
Caligiuri, S. T. Jacob, J. T. Mendell, K. Ghoshal, J. Clin. Invest. 2012, 122,
2871.
[1] X. Z. Zhou, K. P. Lu, Nat. Rev. Cancer 2016, 16, 463.
[2] K. P. Lu, S. D. Hanes, T. Hunter, Nature 1996, 380, 544.
[3] E. S. Yeh, A. R. Means, Nat. Rev. Cancer 2007, 7, 381.
[4] Z. Lu, T. Hunter, Cell Res. 2014, 24, 1033.
[5] L. Bao, A. Kimzey, G. Sauter, J. M. Sowadski, K. P. Lu, D. G. Wang, Am. J.
Pathol. 2004, 164, 1727.
[6] L. Hennig, C. Christner, M. Kipping, B. Schelbert, K. P. Rꢁcknagel, S. Grab-
ley, G. Kꢁllertz, G. Fischer, Biochemistry 1998, 37, 5953.
[7] E. Campaner, A. Rustighi, A. Zannini, A. Cristiani, S. Piazza, Y. Ciani, O.
Kalid, E. Baloglu, S. Shacham, B. Valsasina, U. Cucchi, A. C. Pippione,
M. L. Lolli, B. Giabbai, P. Storici, G. Rossetti, F. Benvenuti, E. Bello, M.
D‘Incalci, E. Cappuzzelli, A. Rosato, G. D. Sal, Nat. Commun. 2017, 8,
15772.
[25] W. C. Tsai, S. D. Hsu, C. S. Hsu, T. C. Lai, S. J. Chen, R. Shen, Y. Huang,
H. C. Chen, C. H. Lee, T. F. Tsai, M. T. Hsu, J. C. Wu, H. D. Huang, M. S.
Shiao, M. Hsiao, A. P. Tsou, J. Clin. Invest. 2012, 122, 2884.
[26] J. Kota, R. R. Chivukula, K. A. O’Donnell, E. A. Wentzel, C. L. Montgomery,
H. W. Hwang, T. C. Chang, P. Vivekanandan, M. Torbenson, K. R. Clark,
J. R. Mendell, J. T. Mendell, Cell 2009, 137, 1005.
[27] Y. Teng, Y. Zhang, K. Qu, X. Yang, J, Fu, W. Chen, X. Li, Oncotarget
2015, 6, 40799.
[28] Y. K. Zhang, H. Wang, Y. Leng, Z. L. Li, Y. F. Yang, F. J. Xiao, Q. F. Li, X. Q.
Chen, L. S. Wang, Biochem. Biophys. Res. Commun. 2011, 414, 233.
[29] D. B. Kitchen, H. Decornez, J. R. Furr, J. Bajorath, Nat. Rev. Drug Discovery
2004, 3, 935.
[8] D. V. Urusova, J. H. Shim, D. Kim, S. Jung, T. A. Zykova, A. Carper, A. M.
Bode, Z. Dong, Cancer Prev. Res. 2011, 4, 1366.
[9] S. Wei, S. Kozono, L. Kats, M. Nechama, W. Z. Li, J. Guarnerio, M. Luo,
M. H. You, Y. D. Yao, A. Kondo, H. Hu, G. Bozkurt, N. J. Moerke, S. Cao, M.
Reschke, C. H. Chen, E. M. Rego, F. LoCoco, L. Cantley, T. H. Lee, H. Wu,
Y. Zhang, P. P. Pandolfi, X. Z. Zhou, K. P. Lu, Nat. Med. 2015, 21, 457.
[10] W. Pu, J. Li, Y. Zheng, X. Shen, X. Fan, J. K. Zhou, J. He, Y. Deng, X. Liu, C.
Wang, S. Yang, Q. Chen, L. Liu, G. Zhang, Y. Q. Wei, Y. Peng, Hepatology
2018, 68, 547.
[11] L. A. Torre, F. Bray, R. L. Siegel, J. Ferlay, J. Lortet-Tieulent, A. Jemal, CA-
Cancer J. Clin. 2015, 65, 87–108.
[12] J. M. Llovet, S. Ricci, V. Mazzaferro, P. Hilgard, E. Gane, J. F. Blanc, A. C.
Oliveira, A. Santoro, J. L. Raoul, A. Forner, M. Schwartz, C. Porta, S.
Zeuzem, L. Bolondi, T. F. Greten, P. R. Galle, J. F. Seitz, I. Borbath, D. Hꢂus-
singer, T. Giannaris, M. Shan, M. Moscovici, D. Voliotis, J. Bruix, N. Engl. J.
Med. 2008, 359, 378.
[30] D. L. Ma, D. S. H. Chan, G. Wei, H. J. Zhong, H. Yang, L. T. Leung, E. A.
Gullen, P. Chiu, Y. C. Cheng, C. H. Leung, Chem. Commun. 2014, 50,
13885.
[13] P. R. Galle, J. Hepatol. 2008, 49, 871.
[14] C. M. Wong, C. C. Wong, J. M. Lee, D. N. Fan, S. L. Au, I. O. Ng, Hepatolo-
gy 2012, 55, 1453.
[15] Y. Peng, C. M. Croce, Signal Transduct. Target. Ther. 2016, 1, 15004.
[16] H. L. Sun, J. K. Zhou, K. Teng, Y. H. Hsiao, K. Nakanishi, M. Fassan, Z. H.
Luo, G. Q. Shi, E. Tili, H. Kutay, F. Lovat, C. Vicentini, H. L. Huang, S. W.
Manuscript received: October 3, 2018
Revised manuscript received: November 1, 2018
Version of record online: && &&, 0000
Chem. Asian J. 2018, 00, 0 – 0
www.chemasianj.org
5
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
Pin1 Inhibitors
Neat as a pin: Prenylated flavonol AF-
39 was discovered as a novel and selec-
tive Pin1 inhibitor with an IC50 value of
1.008 mm. In hepatocellular carcinoma
(HCC) cells, AF-39 significantly suppress-
es HCC proliferation via restoring ERK-
phosphorylated exportin-5 (XPO5) nu-
cleus–cytoplasm distribution and upre-
gulating microRNA biogenesis.
Yuanyuan Zheng, Wenchen Pu, Jiao Li,
Xianyan Shen, Qiang Zhou, Xin Fan,
Sheng-Yong Yang, Yamei Yu, Qiang Chen,
Chun Wang, Xin Wu,* Yong Peng*
&& – &&
Discovery of a Prenylated Flavonol
Derivative as a Pin1 Inhibitor to
Suppress Hepatocellular Carcinoma by
Modulating MicroRNA Biogenesis
&
&
Chem. Asian J. 2018, 00, 0 – 0
www.chemasianj.org
6
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!