The stilbenoid tyrosine kinase inhibitor, G6, suppresses Jak2-V617F-mediated human pathological cell growth in vitro and in vivo

Annet Kirabo, Jennifer Embury, Ró Bert Kiss, Tímea Polgár, Meghanath Gali, Anurima Majumder, Kirpal S. Bisht, Christopher R. Cogle, György M. Keseru, Peter P. Sayeski

Research output: Contribution to journalArticle

Abstract

Using structure-based virtual screening, we previously identified a novel stilbenoid inhibitor of Jak2 tyrosine kinase named G6. Here, we hypothesized that G6 suppresses Jak2-V617F-mediated human pathological cell growth in vitro and in vivo. We found that G6 inhibited proliferation of the Jak2-V617F expressing human erythroleukemia (HEL) cell line by promoting marked cell cycle arrest and inducing apoptosis. The G6-dependent increase in apoptosis levels was concomitant with increased caspase 3/7 activity and cleavage of PARP. G6 also selectively inhibited phosphorylation of STAT5, a downstream signaling target of Jak2. Using a mouse model of Jak2-V617F-mediated hyperplasia, we found that G6 significantly decreased the percentage of blast cells in the peripheral blood, reduced splenomegaly, and corrected a pathologically low myeloid to erythroid ratio in the bone marrow by eliminating HEL cell engraftment in this tissue. In addition, drug efficacy correlated with the presence of G6 in the plasma, marrow, and spleen. Collectively, these data demonstrate that the stilbenoid compound, G6, suppresses Jak2-V617F-mediated aberrant cell growth. As such, G6 may be a potential therapeutic lead candidate against Jak2-mediated, human disease. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Original languageEnglish
Pages (from-to)4280-4291
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number6
DOIs
Publication statusPublished - 11 Feb 2011

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    Kirabo, A., Embury, J., Kiss, R. B., Polgár, T., Gali, M., Majumder, A., Bisht, K. S., Cogle, C. R., Keseru, G. M., & Sayeski, P. P. (2011). The stilbenoid tyrosine kinase inhibitor, G6, suppresses Jak2-V617F-mediated human pathological cell growth in vitro and in vivo. Journal of Biological Chemistry, 286(6), 4280-4291. https://doi.org/10.1074/jbc.M110.200774