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

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