title: Dehydrocrenatidine is a novel janus kinase inhibitor.
abstract: 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.
authors.affiliation: Schools of Life Sciences and Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Schools of Life Sciences and Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhu
authors.affiliation: Schools of Life Sciences and Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Du
authors.affiliation: Schools of Life Sciences and Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Bai
authors.affiliation: Schools of Life Sciences and Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Schools of Life Sciences and Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Nan
authors.affiliation: Schools of Life Sciences and Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Qin
authors.affiliation: Schools of Life Sciences and Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Schools of Life Sciences and Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Hou
authors.affiliation: Schools of Life Sciences and Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Schools of Life Sciences and Basic Medical Sciences, Lanzhou University, Lanzhou, China yangjb@lzu.edu.cn.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Yang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D062126:Databases, Chemical; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D002243:Carbolines; D016898:Interferon-alpha; D015850:Interleukin-6; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C000597852:dehydrocrenatidine; D007371:Interferon-gamma; D053614:Janus Kinase 2