The most direct strategy for blocking NF-κB activation is to block NF-κB from binding to specific κB sites on DNA. Some sesquiterpene lactones (SLs) have been reported to inhibit NF-κB [119] by interacting with Cys-38 in the DNA-binding loop of RelA [120, 121]. Most SLs can also inhibit DNA binding through an analogous Cys residue in the DNA-binding loops of p50 and c-Rel. Recently, a computer-based structural comparison of 103 SLs predicted that a methylene-carbonyl substructure is important for SL-based inhibition of RelA at Cys-38 [122]. Some SLs, including parthenolide, have been shown to inhibit IKKβ through the reactive Cys-179 in the kinase activation loop [34, 121]. Thus, SLs, which target both IKK activity and NF-κB subunit DNA binding [36], have multistep inhibitory activity within the NF-κB signaling pathway.
