Development of RelB-Targeting Small Molecule Inhibitors of Non-canonical NF-κB Signaling with Antitumor Efficacy.

Abstract

Dysfunction of the non-canonical NF-κB signaling pathway has been causally associated with numbers of cancers and autoimmune diseases. However, specific inhibitors for this signaling pathway remain to be developed. Here we showed that structure-based cell-based screening yielded a potent and specific small molecule targeting RelB to inhibit non-canonical NF-κB signaling pathway, while had no inhibitory effect on canonical NF-κB signaling pathway. Mechanistically, the inhibitor directly interacted with RelB protein and disrupted RelB binding to its target DNA, thus repressing RelB transactivity on target genes. Through blocking oncogenic activity of non-canonical NF-κB signaling pathway in colorectal cancer or B lymphoma, the inhibitor efficiently exerted a potent antitumor effect in vitro and in vivo. Thus, our study provided new RelB-targeting inhibitor that inhibited non-canonical NF-κB signaling pathway and facilitated precise therapeutic applications in cancers and possibly other diseases.