Identification of a Novel Inhibitor of the NF-κB Pathway

NF-κB1 plays a central role in regulating genes involved in inflammatory responses, and its recently described role in oncogenesis reemphasizes its importance as a critical mediator of cellular function. We describe herein a novel inhibitor (MOL-294) of NF-κB driven transcription that does not inhibit the proteasome complex, does not inhibit IκB2 phosphorylation, and does not significantly inhibit nuclear translocation of the p65 / RelA subunit of NF-κB. We have identified thioredoxin, a cellular redox protein, which has previously been implicated in the regulation of NF-κB driven transcription, as one of the intracellular targets of MOL-294. The identification of a low molecular weight inhibitor of this type of redox protein represents a novel mechanism of inhibiting the NF-κB signaling pathway.