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

Dong, T.; Li, C.; Wang, X.; Dian, L.; Zhang, X.; Chen, X.; Li, L.; Cao, R.; Huang, N.; He, S. *; Lei, X.*
Nature Commun. 2015, 6, 6522

Aberrant activation of NF-kB is associated with the development of cancer and autoimmune and inflammatory diseases. IKKs are well recognized as key regulators in the NF-kB 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-kB […]

Aberrant activation of NF-kB is associated with the development of cancer and autoimmune and inflammatory diseases. IKKs are well recognized as key regulators in the NF-kB 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-kB pathway. Ainsliadimer A selectively binds to the conserved cysteine 46 residue of IKKa/b and suppresses their activities through an allosteric effect, leading to the inhibition of?both canonical and non-canonical NF-kB 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 IKKa/b to block NF-kB signalling. Therefore, it has great potential for use in the development of anticancer and anti-inflammatory therapies.

Link: http://www.nature.com/ncomms/2015/150327/ncomms7522/full/ncomms7522.html