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

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.

• Authors: Ting Dong, Chao Li, Xing Wang, Longyang Dian, Xiuguo Zhang, Lin Li, She Chen, Ran Cao, Li Li, Niu Huang, Sudan He, Xiaoguang Lei
• Journal: Nature communications (Nat Commun) Vol. 6 Pg. 6522 (Mar 27 2015) ISSN: 2041-1723 [Electronic] England
• PMID: 25813672 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lactones
• NF-kappa B
• Sesquiterpenes
• ainsliadimer A
• I-kappa B Kinase
• Cysteine

Topics

• Allosteric Regulation
• Allosteric Site
• Amino Acid Sequence
• Animals
• Cell Line, Tumor
• Conserved Sequence
• Cysteine (metabolism)
• HEK293 Cells
• HeLa Cells
• Humans
• I-kappa B Kinase (drug effects, metabolism)
• Lactones (metabolism, pharmacology)
• Mice
• NF-kappa B (drug effects, metabolism)
• Neoplasms (metabolism)
• RAW 264.7 Cells
• Sesquiterpenes (metabolism, pharmacology)
• Signal Transduction (drug effects)