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ACS Medicinal Chemistry Letters
Expert opinion on therapeutic targets 2004, 8, 409.
(6) Bowman, T.; Garcia, R.; Turkson, J.; Jove, R. STATs in oncogenesis.
Oncogene 2000, 19, 2474.
Cultures of melanoma cells harboring aberrantlyꢀactive STAT3
(C8161, 1205LU, and C81ꢀ61) and counterpart that does not
(AR7119) were treated with 1a or 1c at the indicated concentraꢀ
tions for 72 h and subjected to MTT assay for viable cells, which
were plotted as % viability; (E) Human breast cancer MDAꢀMBꢀ
231 cells were seeded as singleꢀcell culture and treated once with
0ꢀ3 ꢁM of the indicated compounds and allowed to culture until
large colonies were visible, which were stained with crystal violet,
counted and plotted; and (F) human breast cancer, MDAꢀMBꢀ231
cells in culture were wounded and treated once with or without 8
µM of the indicated compounds and allowed to migrate to the
denuded area over a 23ꢀh period and imaged. Control (0) repreꢀ
sents 0.05% DMSOꢀtreated cells. Values, mean ± S.D. of 3 indeꢀ
pendent determinations. Data are representative of 3 independent
determinations. *p<0.01, **p<0.005, ***p<0.001.
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(7) Zhang, X.; Yue, P.; Fletcher, S.; Zhao, W.; Gunning, P. T.; Turkson,
J. A novel smallꢀmolecule disrupts Stat3 SH2 domainꢀ
phosphotyrosine interactions and Stat3ꢀdependent tumor processes.
Biochem Pharmacol 2010, 79, 1398.
(8) Zhang, X.; Yue, P.; Page, B. D.; Li, T.; Zhao, W.; Namanja, A. T.;
Paladino, D.; Zhao, J.; Chen, Y.; Gunning, P. T.; Turkson, J. Orally
bioavailable smallꢀmolecule inhibitor of transcription factor Stat3
regresses human breast and lung cancer xenografts. Proc Natl Acad
Sci U S A 2012, 109, 9623.
(9) Turkson, J.; Ryan, D.; Kim, J. S.; Zhang, Y.; Chen, Z.; Haura, E.;
Laudano, A.; Sebti, S.; Hamilton, A. D.; Jove, R. Phosphotyrosyl
peptides block Stat3ꢀmediated DNA binding activity, gene
regulation, and cell transformation. J Biol Chem 2001, 276, 45443.
(10) Chen, J.; Bai, L.; Bernard, D.; NikolovskaꢀColeska, Z.; Gomez, C.;
Zhang, J.; Yi, H.; Wang, S. StructureꢀBased Design of
Conformationally Constrained, CellꢀPermeable STAT3 Inhibitors.
ACS Med Chem Lett. 2010 1, 85.
(11) Chen, J.; NikolovskaꢀColeska, Z.; Yang, C.ꢀY.; Gomez, C.; Gao, W.;
Krajewski, K.; Jiang, S.; Roller, P.; Wang, S. Design and synthesis of
a new, conformationally constrained, macrocyclic smallꢀmolecule
inhibitor of STAT3 via 'click chemistry'. Bioorg. Med. Chem. Lett.
2007, 17, 3939.
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ASSOCIATED CONTENT
Supporting Information
Information on compound synthesis, chemical data, the experiꢀ
mental procedures for nuclear extract preparation, gel shift assay,
immunoblotting analysis, cell proliferation, viability assay, and
trypan blue exclusion/phaseꢀcontrast microscopy, clonogenic
survival assay, and the scratch assay is available free of charge on
the ACS Publications website.
(12) Zheng, H.; Hong, H.; Zhang, L.; Cai, X.; Hu, M.; Cai, Y.; Zhou, B.;
Lin, J.; Zhao, C.; Hu, W. Nifuratel, a novel STAT3 inhibitor with
potent activity against human gastric cancer cells. Cancer Manag Res
2017, 9, 565.
(13) Kolosenko, I.; Yu, Y.; Busker, S.; Dyczynski, M.; Liu, J.;
Haraldsson, M.; Palm Apergi, C.; Helleday, T.; Tamm, K. P.; Page,
B. D. G.; Grander, D. Identification of novel small molecules that
inhibit STAT3ꢀdependent transcription and function. PLoS One 2017,
12, e0178844.
(14) Debnath, B.; Xu, S.; Neamati, N. Small molecule inhibitors of signal
transducer and activator of transcription 3 (Stat3) protein. J Med
Chem 2012, 55, 6645.
(15) Oh, D. Y.; Lee, S. H.; Han, S. W.; Kim, M. J.; Kim, T. M.; Kim, T.
Y.; Heo, D. S.; Yuasa, M.; Yanagihara, Y.; Bang, Y. J. Phase I study
of OPBꢀ31121, an Oral STAT3 Inhibitor, in Patients with Advanced
Solid Tumors. Cancer Res Treat. 2015, 47, 607.
(16) Bendell, J. C.; Hong, D. S.; Burris, H. A., 3rd; Naing, A.; Jones, S.
F.; Falchook, G.; Bricmont, P.; Elekes, A.; Rock, E. P.; Kurzrock, R.
Phase 1, openꢀlabel, doseꢀescalation, and pharmacokinetic study of
STAT3 inhibitor OPBꢀ31121 in subjects with advanced solid tumors.
Cancer Chemother Pharmacol. 2014, 74, 125.
(17) Xiao, H.; Bid, H. K.; Jou, D.; Wu, X.; Yu, W.; Li, C.; Houghton, P.
J.; Lin, J. A novel small molecular STAT3 inhibitor, LY5, inhibits
cell viability, cell migration, and angiogenesis in medulloblastoma
cells. J Biol Chem. 2015, 290, 3418.
(18) Yu, W.; Li, C.; Zhang, W.; Xia, Y.; Li, S.; Lin, J. Y.; Yu, K.; Liu, M.;
Yang, L.; Luo, J.; Chen, Y.; Sun, H.; Kong, L. Discovery of an
Orally Selective Inhibitor of Signal Transducer and Activator of
Transcription 3 Using Advanced Multiple Ligand Simultaneous
Docking. J Med Chem. 2017, 60, 2718.
(19) Yue, P.; LopezꢀTapia, F.; Paladino, D.; Li, Y.; Chen, C.ꢀH.; Namanja,
A. T.; Hilliard, T.; Chen, Y.; Tius, M.; Turkson, J. Hydroxamic acid
and benzoic acidꢀbased Stat3 inhibitors suppress human glioma and
breast cancer phenotypes in vitro and in vivo. Cancer Res. 2016, 76,
652.
(20) Zhang, X.; Sun, Y.; Pireddu, R.; Yang, H.; Urlam, M. K.; Lawrence,
H. R.; Guida, W. C.; Lawrence, N. J.; Sebti, S. M. A novel inhibitor
of STAT3 homodimerization selectively suppresses STAT3 activity
and malignant transformation. Cancer Res 2013, 73, 1922.
(21) Serajuddin, A. T. Salt formation to improve drug solubility. Adv Drug
Deliv Rev 2007, 59, 603.
AUTHOR INFORMATION
Corresponding Author
#Address correspondence to: James Turkson, Professor and Proꢀ
gram Director, Cancer Biology Program, University of Hawaii
Cancer Center, 701 Ilalo Street, Suite 344, Honolulu, HI 96813,
Tel. 808ꢀ356ꢀ5784, Fax 808ꢀ587ꢀ0742; Email: jturkꢀ
Author Contributions
The manuscript was written through contributions of all authors. /
All authors have given approval to the final version of the manuꢀ
script. / *These authors contributed equally.
Funding Sources
This work was supported by the NIH/NCI Grant CA161931 (JT),
CA208851 (JT), and University of Hawaii startꢀup funds.
ACKNOWLEDGMENT
We thank all colleagues and members of our laboratory for the
stimulating discussions. Part of the services for this work was
provided by the Chemical Biology Core, which is supported in
part by grant 4P30CA071789 from the NIH/NCI to the University
of Hawaii Cancer Center.
ABBREVIATIONS
STAT, signal transducer and activator of transcription; EMSA,
electrophoretic mobility shift assay; MAPK, mitogenꢀactivated
protein kinase; ERK, extracellular signalꢀregulated kinases.
REFERENCES
(1) Darnell, J. E. Validating Stat3 in cancer therapy. Nat Med. 2005, 11,
595.
(2) Yu, H.; Jove, R. The STATS of CancerꢀNew molecular targets come
of age. Nat. Rev. Cancer 2004, 4, 97.
(3) Yue, P.; Turkson, J. Targeting STAT3 in cancer: how successful are
we? Expert Opin Investig Drugs. 2009, 18 45.
(4) Miklossy, G.; Hilliard, T. S.; Turkson, J. Therapeutic modulators of
STAT signaling for human diseases. Nature Reviews Drug Discovery
2013, 12, 611.
(22) Klein, S. The use of biorelevant dissolution media to forecast the in
vivo performance of a drug. AAPS J. 2010 12, 397.
(23) de Groot, M. J.; Ackland, M. J.; Horne, V. A.; Alex, A. A.; Jones, B.
C. A novel approach to predicting P450 mediated drug metabolism.
CYP2D6 catalyzed Nꢀdealkylation reactions and qualitative
metabolite predictions using a combined protein and pharmacophore
model for CYP2D6. J Med Chem 1999, 42, 4062.
(5) Turkson, J. STAT proteins as novel targets for cancer drug discovery.
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