Janus kinase (JAK) 2 plays a pivotal role in the tumorigenesis of signal transducers and activators of transcription (STAT) 3 constitutively activated solid tumors. JAK2 mutations are involved in the pathogenesis of various types of hematopoietic disorders, such as myeloproliferative disorders, polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Thus, small-molecular inhibitors targeting JAK2 are potent for therapy of these diseases.
METHODS AND RESULTS:
In this study, we screened 1,062,608 drug-like molecules from the ZINC database and 2080 natural product chemicals. We identified a novel JAK family kinase inhibitor, Dehydrocrenatidine, that inhibits JAK-STAT3-dependent DU145 and MDA-MB-468 cell survival and induces cell apoptosis. Dehydrocrenatidine represses constitutively activated JAK2 and STAT3, as well as interleukin-6-, interferon-α-, and interferon-γ-stimulated JAK activity, and STAT phosphorylation, and suppresses STAT3 and STAT1 downstream gene expression. Dehydrocrenatidine inhibits JAKs-JH1 domain overexpression-induced STAT3 and STAT1 phosphorylation. In addition, Dehydrocrenatidine inhibits JAK2-JH1 kinase activity in vitro. Importantly, Dehydrocrenatidine does not show significant effect on Src overexpression and epidermal growth factor-induced STAT3 activation.
CONCLUSIONS:
Our results indicate that Dehydrocrenatidine is a JAK-specific inhibitor. |
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