2. Academic Validation
  3. Development of RelB-targeting small-molecule inhibitors of non-canonical NF-κB signaling with antitumor efficacy

Development of RelB-targeting small-molecule inhibitors of non-canonical NF-κB signaling with antitumor efficacy

  • Mol Ther. 2025 Apr 2;33(4):1519-1534. doi: 10.1016/j.ymthe.2025.01.048.
Cuifeng Li 1,  Shuqi Wei 2,  Donglin Sun 3,  Zhuo Yang 4,  Qi Wang 5,  Han Lin 2,  Haohao Zhang 5,  Yiming Hu 5,  Dandan Liu 5,  Deji Ye 5,  Yu Tao 6,  Zhanjie Liu 6,  Zhijian Xu 4,  Bo Li 4,  Lingling Li 6,  Jie Zhang 6,  Xi Chen 5,  Ningxia Xie 5,  Yufang Shi 6,  Sanhong Liu 7,  Yongzhong Liu 8,  Yuhang Jiang 9,  Weiliang Zhu 10,  Xiaoren Zhang 11
Affiliations

Affiliations

  • 1 The Second Affiliated Hospital, The Sixth Affiliated Hospital, Affiliated Cancer Hospital and Institute, GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, Guangzhou 510000, China; CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 2 The Second Affiliated Hospital, The Sixth Affiliated Hospital, Affiliated Cancer Hospital and Institute, GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, Guangzhou 510000, China.
  • 3 The Second Affiliated Hospital, The Sixth Affiliated Hospital, Affiliated Cancer Hospital and Institute, GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, Guangzhou 510000, China; Department of Urology, Shenzhen Hospital, Southern Medical University, Shenzhen 518000, China.
  • 4 CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 The Second Affiliated Hospital, The Sixth Affiliated Hospital, Affiliated Cancer Hospital and Institute, GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, Guangzhou 510000, China; CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 6 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 7 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 8 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200032, China.
  • 9 The Second Affiliated Hospital, The Sixth Affiliated Hospital, Affiliated Cancer Hospital and Institute, GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, Guangzhou 510000, China; CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, China. Electronic address: xhaka2016@163.com.
  • 10 CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: wlzhu@simm.ac.cn.
  • 11 The Second Affiliated Hospital, The Sixth Affiliated Hospital, Affiliated Cancer Hospital and Institute, GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, Guangzhou 510000, China; CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: xrzhang@gzhmu.edu.cn.
PMID: 39910816 DOI: 10.1016/j.ymthe.2025.01.048
Abstract

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.

Keywords

B lymphoma; RS47; RelB; colorectal cancer; inhibitor; non-canonical NF-κB; tumorigenesis.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-171579
    NF-κB Inhibitor