Molecular Design and Biological Activities of NF-κB Inhibitors

NF-κB is a transcription factor that induces inflammatory cytokines and anti-apoptotic proteins. We designed a new NF-κB inhibitor that is based on the structure of the antibiotic epoxyquinomicin C. The designed compound, dehydroxymethyl-epoxyquino-micin (DHMEQ), inhibited the TNF-α-induced activation of NF-κB, and showed an anti-arthritic effect in mice. Recently, we looked into its mechanism of inhibition. DHMEQ inhibited the TNF-α-induced cellular DNA binding of nuclear NF-κB, but not the phosphorylation or degradation of I-κB. Moreover, DHMEQ inhibited the TNF-α-induced nuclear accumulation of p65, a component of NF-κB. On the other hand, DHMEQ did not inhibit the nuclear transport of Smad2 and the large T antigen. Also, it did not inhibit the TNF-α-induced activation of JNK, but synergisti-cally induced apoptosis with TNF-α in human T cell leukemia Jurkat cells. Therefore, DHMEQ specifically inhibited the NF-κB-activating pathway in the TNF-α-treated cells. Taken together, our data show that DHMEQ is a unique inhibitor of NF-κB that acts at the level of the nuclear translocation. It may be useful as an anti-inflammatory and anticancer agent.