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Ainsliadimer A selectively inhibits IKKα/β by covalently binding a conserved cysteine

Author

Listed:
  • Ting Dong

    (Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences
    National Institute of Biological Sciences (NIBS))

  • Chao Li

    (Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University)

  • Xing Wang

    (Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, and Collaborative Innovation Center of Hematology, Soochow University)

  • Longyang Dian

    (National Institute of Biological Sciences (NIBS))

  • Xiuguo Zhang

    (National Institute of Biological Sciences (NIBS))

  • Lin Li

    (National Institute of Biological Sciences (NIBS))

  • She Chen

    (National Institute of Biological Sciences (NIBS))

  • Ran Cao

    (National Institute of Biological Sciences (NIBS))

  • Li Li

    (National Institute of Biological Sciences (NIBS))

  • Niu Huang

    (National Institute of Biological Sciences (NIBS))

  • Sudan He

    (Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, and Collaborative Innovation Center of Hematology, Soochow University)

  • Xiaoguang Lei

    (Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences
    National Institute of Biological Sciences (NIBS)
    Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University)

Abstract

Aberrant activation of NF-κB is associated with the development of cancer and autoimmune and inflammatory diseases. IKKs are well recognized as key regulators in the NF-κB pathway and therefore represent attractive targets for intervention with small molecule inhibitors. Herein, we report that a complex natural product ainsliadimer A is a potent inhibitor of the NF-κB pathway. Ainsliadimer A selectively binds to the conserved cysteine 46 residue of IKKα/β and suppresses their activities through an allosteric effect, leading to the inhibition of both canonical and non-canonical NF-κB pathways. Remarkably, ainsliadimer A induces cell death of various cancer cells and represses in vivo tumour growth and endotoxin-mediated inflammatory responses. Ainsliadimer A is thus a natural product targeting the cysteine 46 of IKKα/β to block NF-κB signalling. Therefore, it has great potential for use in the development of anticancer and anti-inflammatory therapies.

Suggested Citation

  • Ting Dong & Chao Li & Xing Wang & Longyang Dian & Xiuguo Zhang & Lin Li & She Chen & Ran Cao & Li Li & Niu Huang & Sudan He & Xiaoguang Lei, 2015. "Ainsliadimer A selectively inhibits IKKα/β by covalently binding a conserved cysteine," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7522
    DOI: 10.1038/ncomms7522
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