N-Substituted adenosine analogues,a novel class of JAK2 inhibitors,potently block STAT3 signaling in human cancer cells |
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Authors: | Peng Liu Liwei Zhao Ximing Xu Feng Liu Wenchao Zhang Cheng Zhou Jing Chen Yanlong Pan Yuping Du Jinbo Yang Qin Wang |
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Affiliation: | 1. Department of Cell Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China;2. Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, Université Paris Diderot, CNRS EAC4413, Paris, France;3. Department of Molecular Genetics, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH 44195, USA |
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Abstract: | The JAK2/STAT3 signaling pathway plays a critical role in oncogenesis and malignancy, which makes it a promising anticancer target. We report four N6-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. |
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Keywords: | N6-Substituted adenosine analogues JAK2 inhibitors STAT3 Apoptosis Targeted therapy |
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