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Novel synthetic bisindolylmaleimide alkaloids inhibit STAT3 activation by binding to the SH2 domain and suppress breast xenograft tumor growth

Oncogene volume 37, pages 2469–2480 (2018)Cite this article

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Abstract

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in malignant tumors and plays important roles in multiple aspects of cancer aggressiveness. Thus, targeting STAT3 promises to be an attractive strategy for the treatment of advanced metastatic tumors. Bisindolylmaleimide alkaloid (BMA) has been shown to have anti-cancer activities and was thought to suppress tumor cell growth by inhibiting protein kinase C. In this study, we show that a newly synthesized BMA analog, BMA097, is effective in suppressing tumor cell and xenograft growth and in inducing spontaneous apoptosis. We also provide evidence that BMA097 binds directly to the SH2 domain of STAT3 and inhibits STAT3 phosphorylation and activation, leading to reduced expression of STAT3 downstream target genes. Structure activity relationship analysis revealed that the hydroxymethyl group in the 2,5-dihydropyrrole-2,5-dione prohibits STAT3 inhibitory activity of BMA analogs. Altogether, we conclude that the synthetic BMA analogs may be developed as anti-cancer drugs by targeting and binding to the SH2 domain of STAT3 and inhibiting the STAT3 signaling pathway.

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Acknowledgements

We thank IU Big Red supercomputers for the CPU time. This work was supported in part by grants from the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT, No IRT_17R68), the National Natural Science Foundation of China (Nos. 81273532 & U1501221) and by National Institute of Health Grant R01 CA211904.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA

    Xia Li, Yifan Chen, Zizheng Dong, Jing-Yuan Liu & Jian-Ting Zhang

  2. School of Ocean, Shandong University, Weihai, China

    Xia Li, Lin Li & Xiao Sun

  3. Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China

    Hongguang Ma & Weiming Zhu

  4. Department of Computer and Information Science, Indiana University-Purdue University, Indianapolis, IN, USA

    Jing-Yuan Liu

  5. IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA

    Jian-Ting Zhang

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  1. Xia Li
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Correspondence to Xia Li, Jing-Yuan Liu, Weiming Zhu or Jian-Ting Zhang.

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Li, X., Ma, H., Li, L. et al. Novel synthetic bisindolylmaleimide alkaloids inhibit STAT3 activation by binding to the SH2 domain and suppress breast xenograft tumor growth. Oncogene 37, 2469–2480 (2018). https://doi.org/10.1038/s41388-017-0076-0

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