A46, a benzothiophene-derived compound, suppresses Jak2-mediated pathologic cell growth.
Hyperkinetic Jak2 tyrosine kinase signaling has been implicated in several hematological disorders, including myeloproliferative neoplasms. Effective Jak2 inhibitors can have significant therapeutic potential. Here, using structure-based virtual screening, we identified a benzothiophene-derived Jak2 inhibitor named A46. We hypothesized that this compound would inhibit Jak2-V617F-mediated pathologic cell growth. To test this, A46 was analyzed for its ability to inhibit recombinant Jak2 protein catalysis; suppress Jak2-mediated pathogenic cell growth in vitro; inhibit the aberrant ex vivo growth of Jak2-V617F-expressing primary human bone marrow cells; and inhibit Jak2-mediated pathogenesis in vivo. To this end, we found that A46 selectively inhibited Jak2-V617F protein when compared to wild-type Jak2 protein. The drug also selectively inhibited the proliferation of Jak2-V617F-expressing cells in both a time- and dose-dependent manner, and this correlated with decreased Jak2 and signal transducers and activators of transcription 5 phosphorylation within treated cells. The Jak2-V617F cell growth inhibition correlated with an induction of cell cycle arrest and promotion of apoptosis. A46 also inhibited the pathologic growth of primary Jak2-V617F-expressing bone marrow cells ex vivo. Lastly, using a mouse model of Jak2-V617F-mediated myeloproliferative neoplasia. A46 significantly reduced the splenomegaly and megakaryocytic hyperplasia in the spleens of treated mice and the levels of interleukin-6 in the plasma. Collectively, our data demonstrate that the benzothiophene-based compound, A46, suppresses Jak2-mediated pathogenesis, thereby making it a potential candidate drug against Jak2-mediated disorders.
Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Anurima
A
Majumder
Andrew T
AT
Magis
Sung O
SO
Park
Nicholas C
NC
Figueroa
Rebekah
R
Baskin
Annet
A
Kirabo
Robert W
RW
Allan
Zhizhuang Joe
ZJ
Zhao
Kirpal S
KS
Bisht
György M
GM
Keseru
Peter P
PP
Sayeski
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D055162:Biocatalysis; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C569598:1-benzothiophen-2-yl-(4-dimethylaminophenyl)methanol; D013876:Thiophenes; C507924:JAK2 protein, human; D053614:Janus Kinase 2