TY - JOUR T1 - Dehydrocrenatidine Is a Novel Janus Kinase Inhibitor JF - Molecular Pharmacology JO - Mol Pharmacol SP - 572 LP - 581 DO - 10.1124/mol.114.095208 VL - 87 IS - 4 AU - Jing Zhang AU - Ning Zhu AU - Yuping Du AU - Qifeng Bai AU - Xing Chen AU - Jing Nan AU - Xiaodong Qin AU - Xinxin Zhang AU - Jianwen Hou AU - Qin Wang AU - Jinbo Yang Y1 - 2015/04/01 UR - http://molpharm.aspetjournals.org/content/87/4/572.abstract N2 - 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. 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. Our results indicate that dehydrocrenatidine is a JAK-specific inhibitor. ER -