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

Ting Dong, Chao Li, Xing Wang, Longyang Dian, Xiuguo Zhang, Lin Li, She Chen, Ran Cao, Li Li, Niu Huang, Sudan He () and Xiaoguang Lei ()
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Ting Dong: Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences
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

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7522

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