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Inhibition of IB Kinase-Nuclear Factor-B Signaling Pathway by 3,5-Bis(2-flurobenzylidene)piperidin-4-one (EF24), a Novel Monoketone Analog of Curcumin

Graduate Programs in Genetics and Molecular Biology (A.L.K.) and Molecular and Systems Pharmacology (S.L.T.), Departments of Pharmacology (Y.D., J.Z., H.F.), Hematology and Oncology (S.-Y.S., F.R.K., M.S.), and Chemistry (A.S., J.P.S., D.L.), and Emory Chemical Biology Discovery Center (Y.D., A.S., J.P.S., D.L., H.F.), Emory University, Atlanta, Georgia; and Division of Oral Biology and Medicine, University of California Los Angeles Dentistry, Los Angeles, California (C.-Y.W.)

The nuclear factor-B (NF-B) signaling pathway has been targeted for therapeutic applications in a variety of human diseases, includuing cancer. Many naturally occurring substances, including curcumin, have been investigated for their actions on the NF-B pathway because of their significant therapeutic potential and safety profile. A synthetic monoketone compound termed 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24) was developed from curcumin and exhibited potent anticancer activity. Here, we report a mechanism by which EF24 potently suppresses the NF-B signaling pathway through direct action on IB kinase (IKK). We demonstrate that 1) EF24 induces death of lung, breast, ovarian, and cervical cancer cells, with a potency about 10 times higher than that of curcumin; 2) EF24 rapidly blocks the nuclear translocation of NF-B, with an IC₅₀ value of 1.3 µM compared with curcumin, with an IC₅₀ value of 13 µM; 3) EF24 effectively inhibits tumor necrosis factor (TNF)--induced IB phosphorylation and degradation, suggesting a role of this compound in targeting IKK; and 4) EF24 indeed directly inhibits the catalytic activity of IKK in an in vitro-reconstituted system. Our study identifies IKK as an effective target for EF24 and provides a molecular explanation for a superior activity of EF24 over curcumin. The effective inhibition of TNF--induced NF-B signaling by EF24 extends the therapeutic application of EF24 to other NF-B-dependent diseases, including inflammatory diseases such as rheumatoid arthritis.

Received for publication February 10, 2008.

Accepted for publication June 23, 2008.

Address correspondence to: Dr. Haian Fu, Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322. E-mail: hfu{at}emory.edu

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