RT Journal Article
SR Electronic
T1 Dehydrocrenatidine Is a Novel Janus Kinase Inhibitor
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 572
OP 581
DO 10.1124/mol.114.095208
VO 87
IS 4
A1 Jing Zhang
A1 Ning Zhu
A1 Yuping Du
A1 Qifeng Bai
A1 Xing Chen
A1 Jing Nan
A1 Xiaodong Qin
A1 Xinxin Zhang
A1 Jianwen Hou
A1 Qin Wang
A1 Jinbo Yang
YR 2015
UL http://molpharm.aspetjournals.org/content/87/4/572.abstract
AB 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.