Sunday, March 29, 2015

​Ainsliadimer A is a Natural Potent Inhibitor of NF-κB Pathways

Ainsliadimer A acts as a Natural Potent Inhibitor of NF-κB Pathways

The evolutionarily conserved nuclear factor-kB (NF-kB) signalling pathway plays key roles in inflammatory and immune responses and in cell survival by regulating the transcription of numerous target genes. Aberrant activation of the NF-kB signalling pathway is known to be involved in a variety of human diseases including cancer, autoimmune diseases and chronic inflammatory diseases. The NF-kB pathway is important for cancer development and progression, in that it regulates a wide variety of target genes involved in cell proliferation, cell survival, invasion, angiogenesis and metastasis. Continuous activation of NF-kB is a common feature in the majority of human cancers, including both solid and haematopoietic malignancies [1].

In addition to its critical role in cancer, enhanced NF-kB activity is a hallmark of various autoimmune and inflammatory diseases. Chronic inflammatory conditions have been shown to drive an increased cancer risk. Examples of this include colitis-associated colon cancer and hepatitis-associated liver cancer.

Ainsliadimer A represents the first small molecule natural product targeting the functional C46 of IKKa/IKKß. Ainsliadimer A leads to IKKa/IKKß inactivation through a novel allosteric effect. Moreover, Ainsliadimer A powerfully blocks LPS-mediated inflammatory responses and tumour growth in vivo. These discoveries not only indicate that Ainsliadimer A indeed acts as a potent inhibitor of IKKa/ß, but also reveal that Ainsliadimer A could be used as a lead compound in the development of new therapeutic agents for the treatment of cancer and inflammatory disorders.
Ainsliadimer A

Ainsliadimer A was originally isolated from Ainsliaea macrocephala, a plant that has been used in traditional Chinese medicine for the treatment of various diseases, including angina and rheumatoid arthritis. The first enantioselective total syntheses of Ainsliadimer A, as well as that of other related dimeric and trimeric sesquiterpenoids is reported in literature [1].

Important finding about Ainsliadimer A:

1. Ainsliadimer A inhibits LPS-induced inflammatory cytokines in vivo.
2. Ainsliadimer A acts as a potent inhibitor of NF-kB pathways.
3. Ainsliadimer A directly targets two kinase, namely IKKa and IKKß. Moreover, it is a novel allosteric inhibitor of these two kinases.
4. Ainsliadimer A inhibits tumour growth.
5. Ainsliadimer A represents the first small molecule that blocks NF-kB by directly targeting C46 of IKKa/ß. The putative allosteric site around C46, most likely unique to IKKa/ß, confers the high selectivity of Ainsliadimer A for IKKa/ß, thereby tending to have low non-specific toxicity and a high therapeutic index.

The authors conclude with " in both in vitro and in vivo studies, Ainsliadimer A was shown to be a promising agent against the survival of cancer cells, tumour growth and endotoxin-mediated inflammatory responses. It is tempting to speculate that this unique inhibitory effect of Ainsliadimer A on IKKa/ß should be further exploited for the elucidation of uncharacterized mechanisms of IKKa/ß activation, as well as the development of new anticancer and anti-inflammatory therapies".

1. Vallabhapurapu, S.; et. al. Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 2009, 27, 693-733 .
2. Lei, X.; et. al. A Biomimetic Total Synthesis of (+)-Ainsliadimer A. Org Lett 2010, 12(19), 4284-4287.

Article citation: He, S.; et. al. Ainsliadimer A selectively inhibits IKKa/ß by covalently binding a conserved cysteine. Nat Commun 6, Article number: 6522 DOI:10.1038/ncomms7522