A novel small-molecule inhibitor of NF-κB signaling

The inducible transcription factor NF-kappa B regulates divergent signaling pathways including inflammatory response and cancer development. Selective inhibitors for NF-kappa B signaling are potentially useful for treatment of inflammation and cancer. NF-kappa B is canonically activated by preferential disposal of its inhibitory protein; I kappa B, which suppresses the nuclear translocation of NF-kappa B. I kappa B alpha (a major member of I kappa B family proteins) is phosphorylated with an I kappa B kinase (IKK) and subsequently polyubiquitylated by SCF beta TrCP1 ubiquitin-ligase in the presence of E1 and E2 prior to proteasomal degradation. Here, we describe a novel inhibitor termed GS143, which suppressed I kappa B alpha ubiquitylation, but not I kappa B alpha phosphorylation, MDM2-directed p53 ubiquitylation, and proteasome activity in vitro. GS143 markedly suppressed the destruction of I kappa B alpha stimulated by TNF alpha and a set of downstream responses coupled to NF-kappa B signaling but not those of p53 and P-catenin in vivo. Our results indicate that GS143 serves as an effective inhibitor of multiple pathways served by NF-kappa B signaling. (C) 2008 Elsevier Inc. All rights reserved.