Molecular therapy : the journal of the American Society of Gene Therapy · 2025
Development of RelB-targeting small-molecule inhibitors of non-canonical NF-κB signaling with antitumor efficacy.
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Li Cuifeng, Wei Shuqi, Sun Donglin, Yang Zhuo, Wang Qi, Lin Han, Zhang Haohao, Hu Yiming, Liu Dandan, Ye Deji, Tao Yu, Liu Zhanjie, Xu Zhijian, Li Bo, Li Lingling, Zhang Jie, Chen Xi, Xie Ningxia, Shi Yufang, Liu Sanhong, Liu Yongzhong, Jiang Yuhang, Zhu Weiliang, Zhang Xiaoren
Аннотация
Dysfunction of the non-canonical nuclear factor κB (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 the non-canonical NF-κB signaling pathway, while it had no inhibitory effect on the 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 the 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 a new RelB-targeting inhibitor that inhibited the non-canonical NF-κB signaling pathway and facilitated precise therapeutic applications in cancers and possibly other diseases.