2. Academic Validation
  3. Development of the first-in-class RNF4 PROTAC degrader as potential therapeutics for hepatocellular carcinoma

Development of the first-in-class RNF4 PROTAC degrader as potential therapeutics for hepatocellular carcinoma

  • Eur J Med Chem. 2026 Apr 5:307:118668. doi: 10.1016/j.ejmech.2026.118668.
Hui Wan 1,  Yihang Liu 1,  Huimin Chang 1,  Kai Zhang 1,  Zhenzhen Li 1,  Haisen Ni 1,  Jie Xu 1,  Bo Pan 2,  Kongkai Zhu 3,  Junchi Hu 1,  Shuai Wang 1,  Dongqin Yang 4,  Xiaobo Wang 5,  Yongjun Dang 6,  Sanyong Zhu 7
Affiliations

Affiliations

  • 1 Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China.
  • 2 Department of Pediatric Cardiology, Children's Hospital of Chongqing Medical University, Chongqing, 401122, China.
  • 3 Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 4 Department of Digestive Diseases, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China.
  • 5 Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China. Electronic address: [email protected].
  • 6 Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China; Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing, 401122, China; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, 400061, China. Electronic address: [email protected].
  • 7 Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China; Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing, 401122, China. Electronic address: [email protected].
PMID: 41687269 DOI: 10.1016/j.ejmech.2026.118668
Abstract

Ring Finger Protein 4 (RNF4) recognizes poly-SUMOylated proteins via its SUMO-Interacting Motifs (SIMs) and subsequently ubiquitinates them, thus effecting some key regulatory proteins involved in Cancer development and progression. Our previous study found RNF4 was a potential target for HCC interruption. However, none of its inhibitor has been developed so far. Targeting RNF4 for degradation, rather than mere binding, emerged as a promising alternative strategy. To this end, we designed, synthesized and evaluated 28 PROTACs targeting RNF4 based on a reported covalent binder. Among them, RD12 was identified as the lead compound through a systematic screening. RD12 showed efficient RNF4 degradation activity as well as potent anti-proliferative activity in multiple HCC cell lines. Notably, it exhibited significant anti-tumour activity in a HCC mouse model without noticeable side effects. Mechanistic studies confirmed RD12 degraded RNF4 via the ubiquitin-proteasome system, and it induced DNA damage and Apoptosis. These findings collectively underscore RD12 as the first pioneering RNF4 degrader and indicate its potential for HCC therapy.

Keywords

Anti-proliferative activity; HCC therapy; PROTACs; Protein degradation; RNF4.

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