Abstract

JAK2 plays pivotal role in the tumorigenesis of STAT3 constitutively activated solid tumors. JAK2 mutations are involved in the pathogenesis of various types of hematopoietic disorders such as myeloproliferative disorders (MPDs), polycythemia vera (PV), essential thoursombocythemia (ET) and primary myelofibrosis (PMF). Thus, small molecular inhibitors targeting JAK2 are potent for therapy of these diseases. In this study, we screened 1,062,608 drug-like molecules from ZINC database and 2080 natural product chemicals. We identified a novel JAK family kinase inhibitor Dehydrocrenatidine. Dehydrocrenatidine 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 IL-6, IFNα and IFNγ stimulated JAKs activity and STATs phosphorylation, suppresses STAT3 and STAT1 downstream gene expression. Dehydrocrenatidine inhibits JAKs-JH1 domain over-expression induced STAT3 and STAT1 phosphorylations. In addition, Dehydrocrenatidine inhibits JAK2-JH1 kinase activity in vitro. Importantly, Dehydrocrenatidine does not show significant effect on Src over-expression and EGF induced STAT3 activation. Our results indicate that Dehydrocrenatidine is a JAK specific inhibitor.