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NF-kB is a transcription factor that induces inflamma-tory cytokines and anti-apoptotic proteins. We de-signed a new NF-kB inhibitor that is based on the structure of the antibiotic epoxyquinomicin C. The designed compound, dehydroxymethyl-epoxyquino-micin (DHMEQ), inhibited the TNF-a-induced activa-tion of NF-kB, and showed an anti-arthritic effect in mice. Recently, we looked into its mechanism of inhibi-tion. DHMEQ inhibited the TNF-a-induced cellular DNA binding of nuclear NF-kB, but not the phos-phorylation or degradation of I-kB. Moreover, DHMEQ inhibited the TNF-a-induced nuclear accu-mulation of p65, a component of NF-kB. 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-a-induced activation of JNK, but synergisti-cally induced apoptosis with TNF-a in human T cell leukemia Jurkat cells. Therefore, DHMEQ specifically inhibited the NF-kB-activating pathway in the TNF-a-treated cells. Taken together, our data show that DHMEQ is a unique inhibitor of NF-kB that acts at the level of the nuclear translocation. It may be useful as an anti-inflammatory and anticancer agent.