%0 Journal Article %T 3-Deoxy-2β,16-dihydroxynagilactone E, a natural compound from Podocarpus nagi , preferentially inhibits JAK2/STAT3 signaling by allosterically interacting with the regulatory domain of JAK2 and induces apoptosis of cancer cells %A Shan Hui %A Yao Sheng %A Ye Yang %A Yu Qiang %J Acta Pharmacologica Sinica %D 2019 %B 2019 %9 %! 3-Deoxy-2β,16-dihydroxynagilactone E, a natural compound from Podocarpus nagi , preferentially inhibits JAK2/STAT3 signaling by allosterically interacting with the regulatory domain of JAK2 and induces apoptosis of cancer cells %K %X The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, especially the JAK2/STAT3 pathway, play vital roles in the development of many malignancies. Overactivation of STAT3 promotes cancer cell survival and proliferation. Therefore, the JAK2/STAT3-signaling pathway has been considered a promising target for cancer therapy. In this study, we identified a natural compound 3-deoxy-2β,16-dihydroxynagilactone E (B6) from the traditional Chinese medicinal plant Podocarpus nagi as a potent inhibitor of STAT3 signaling. B6 preferentially inhibited the phosphorylation of STAT3 by interacting with and inactivating JAK2, the main upstream kinase of STAT3. B6 dose-dependently inhibited IL-6-induced STAT3 signaling with an IC 50 of 0.2 μM. In contrast to other JAK2 inhibitors, B6 did not interact with the catalytic domain but instead with the FERM-SH2 domain of JAK2. This interaction was JAK-specific since B6 had little effect on other tyrosine kinases. Furthermore, B6 potently inhibited the growth and induced apoptosis of MDA-MB-231 and MDA-MB-468 breast cancer cells with overactivated STAT3. Taken together, our study uncovers a novel compound and a novel mechanism for the regulation of JAK2 and offers a new therapeutic approach for the treatment of cancers with overactivated JAK2/STAT3. %U http://www.chinaphar.com/article/view/10063 %V 40 %N 12 %P 1578-1586 %@ 1745-7254