title: N6-substituted adenosine analogues, a novel class of JAK2 inhibitors, potently block STAT3 signaling in human cancer cells.
abstract: The JAK2/STAT3 signaling pathway plays a critical role in oncogenesis and malignancy, which makes it a promising anticancer target. We report four N(6)-substituted adenosine analogues (AAs) as potential JAK2/STAT3 inhibitors identified through a STAT3-based high-throughput drug screening system. These AAs exhibited selective anti-cancer activity on human cancer cells and xenograft tumors with constitutively activated STAT3. They rapidly and potently suppressed constitutive and IL-6/IFN-γ-induced JAK2/STAT3 signal activation. In addition, we finally proved that the STAT3 signal blockage by three of these AAs was dependent on specific JAK2 inhibition. These AAs may represent new targeted therapeutic agents for JAK2/STAT3 hyper-activated human cancers.
authors.affiliation: Department of Cell Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Cell Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, Université Paris Diderot, CNRS EAC4413, Paris, France.
authors.forename: Ximing
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Cell Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Cell Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Cell Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Cell Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Cell Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China; Department of Molecular Genetics, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cell Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China. Electronic address: qwang@lzu.edu.cn.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives*; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D004791:Enzyme Inhibitors; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D053614:Janus Kinase 2; D020169:Caspases; D000241:Adenosine
keywords: Apoptosis; JAK2 inhibitors; N(6)-Substituted adenosine analogues; STAT3; Targeted therapy