A novel small-molecule inhibitor of NF-κB signaling

The inducible transcription factor NF-κB regulates divergent signaling pathways including inflammatory response and cancer development. Selective inhibitors for NF-κB signaling are potentially useful for treatment of inflammation and cancer. NF-κB is canonically activated by preferential disposal of its inhibitory protein; IκB, which suppresses the nuclear translocation of NF-κB. IκBα (a major member of IκB family proteins) is phosphorylated with an IκB kinase (IKK) and subsequently polyubiquitylated by SCFβTrCP1 ubiquitin-ligase in the presence of E1 and E2 prior to proteasomal degradation. Here, we describe a novel inhibitor termed GS143, which suppressed IκBα ubiquitylation, but not IκBα phosphorylation, MDM2-directed p53 ubiquitylation, and proteasome activity in vitro. GS143 markedly suppressed the destruction of IκBα stimulated by TNFα and a set of downstream responses coupled to NF-κB signaling but not those of p53 and β-catenin in vivo. Our results indicate that GS143 serves as an effective inhibitor of multiple pathways served by NF-κB signaling.