The stilbenoid tyrosine kinase inhibitor, G6, suppresses Jak2-V617F-mediated human pathological cell growth in vitro and in vivo.
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.
Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
Annet
A
Kirabo
Jennifer
J
Embury
Róbert
R
Kiss
Tímea
T
Polgár
Meghanath
M
Gali
Anurima
A
Majumder
Kirpal S
KS
Bisht
Christopher R
CR
Cogle
György M
GM
Keseru
Peter P
PP
Sayeski
D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013267:Stilbenes / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; D013267:Stilbenes; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2