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JAK2/STAT3 inhibition slows disease progression in orthotopic
xenografts of human glioblastoma brain tumor stem cells. Neuro
Oncol. 2013, 15, 198-207.
tumors extracted and immunohistochemistry performed
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for pSTAT3, Ki67 (proliferation) and TUNEL (apoptosis).
Analysis of tumors showed decreased tumor cells in 31
treated mice using Hematoxylin/Eosin staining (Fig 5A).
Significantly, 31 decreased pSTAT3 expression in tumor
cells of treated mice (Fig 5B). Furthermore, 31 appears to
decrease proliferation (Fig 5C) and increased apoptosis
(Fig 5D) of treated tumors. Thus, in vivo studies strongly
suggest in vivo potency, and on-target anti-STAT3 activity.
(7) Villalva, C., Martin-Lannerée, S., Cortes, U., Dkhissi, F.,
Wager, M., Le Corf, A., Tourani, J.M., Dusanter-Fourt, I.,
Turhan, A.G., Karayan-Tapon, L. STAT3 is essential for the
maintenance of neurosphere-initiating tumor cells in patients
with glioblastomas: A potential for targeted therapy? Int J Cancer.
2011, 128, 826-838.
(8) Haftchenary, S. Avadisian, M., Gunning, P.T. Towards the
development of small molecule inhibitors of Stat3 dimerization.
Anti-Cancer Drugs. 2011, 22, 115-127.
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In summary, to the best of our knowledge, we have iden-
tified a most potent, non-phosphorylated direct binding
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STAT3 inhibitor, 31 (SH-4-54). 31 exhibited nM K values
for STAT3, showed unprecedented cytotoxicity in human
BTSCs, displayed no toxicity in human fetal astrocytes,
(9) Leong, P.L., Andrews, G.A., Johnson, D.E., Dyer, K.F., Si-
chuan, X., Jeffrey, C.M., Robbins, P.D., Gadiparthi, S., Burke,
N.A., Watkins, S.F., Grandis, J.R. Targeted inhibition of Stat3
with a decoy oligonucleotide abrogates head and neck cancer cell
growth. PNAS. 2003, 7, 4138-4143.
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potently suppressed pSTAT3 with nM IC ’s, inhibited
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STAT3’s downstream targets and showed no discernible
off-target effects at therapeutic doses. Moreover, in vivo, 31
exhibits BBB permeability, potently suppresses glioma
tumour growth and inhibits pSTAT3 in vivo. This work, for
the first time, demonstrates the power of STAT3 inhibitors
for the treatment of BTSCs and validates the therapeutic
efficacy of a STAT3 inhibitor for GBM clinical application.
(10) Chen, X., Vinkemeier, U., Zhao, Y., Jeruzalmi, D., Darnell,
J. E.;Kuriyan, J. Crystal structure of a tyrosine phosphorylated
STAT-1 dimer bound to DNA. Cell. 1998, 93, 827-839.
(11) Xi. S., Gooding, W.E., Grandis, J.R. In vivo Antitumor ef-
ficacy of STAT3 blockade using a transcription factor decoy ap-
proach: Implications for cancer therapy. Oncogene. 2005, 24, 970-
979.
(12) Stahl, N., Farruggella, T.J., Boulton, T.G., Zhong, Z., Dar-
nell, J.E., Yancopoulos, G.D. Choice of STATs and other sub-
strates specified by modular tyrosine-based motifs in cytokine
receptors. Science. 1995, 267, 1349-1353.
Supporting Information Information on synthesis, char-
acterization, detailed results, and experimental procedures
for SPR, Cytotoxicity, BBB permeability and in vivo assays
is in the supporting information. This material is available
(13) Shahani, V.M., Yue, P., Fletcher, S., Sharmeen, S., Sukhai,
M.A., Luu, D.P., Zhang, X., Sun, H., Zhao, W., Schimmer, A.D.,
Turkson, J., Gunning, P.T. Design, Synthesis and in vitro Charac-
terization of Novel Hybrid Peptidomimetic Inhibitors of STAT3
Protein. Bioorg. Med. Chem. 2011, 19, 1823-1838.
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