ainsliadimer-a and Neoplasms

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.

Topics: Allosteric Regulation; Allosteric Site; Amino Acid Sequence; Animals; Cell Line, Tumor; Conserved Sequence; Cysteine; HEK293 Cells; HeLa Cells; Humans; I-kappa B Kinase; Lactones; Mice; Neoplasms; NF-kappa B; RAW 264.7 Cells; Sesquiterpenes; Signal Transduction