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  3. Development of Novel PROTAC RAD51 Degraders as Enhancers of DNA Damage Response for Hepatocellular Carcinoma Treatment

Development of Novel PROTAC RAD51 Degraders as Enhancers of DNA Damage Response for Hepatocellular Carcinoma Treatment

  • J Med Chem. 2026 Feb 26;69(4):3957-3983. doi: 10.1021/acs.jmedchem.5c02624.
Jinbo Huang 1 2 3,  Haiyu Wang 1 2 3,  Daohong Jiang 1 2 3,  Longjiang Di 1 2 3,  Jiayi Chen 1 2 3,  Yuanqing Sun 1 2 3,  Zhongyi Xie 1 2 3,  Jun Zhang 1 2 3,  Tingting Feng 1 2 3,  Yerkezhan Yerkinkazhina 1 2 3,  Yan Zhou 1 2 3,  Jinqin Qian 4,  Yuxin Shu 5,  Wei-Guo Zhu 1 2 3 5
Affiliations

Affiliations

  • 1 Institute of Gerontology, The First Affiliated Hospital of Shenzhen University; International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Health Science Centre School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China.
  • 2 Shenzhen University School of Pharmacy, Shenzhen University Medical School, Shenzhen 518055, China.
  • 3 National Engineering Research Centrer for Biotechnology, Shenzhen 518055, China.
  • 4 Department of Urology, Peking University First Hospital, Beijing 100035, China.
  • 5 School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui 241002, China.
PMID: 41666241 DOI: 10.1021/acs.jmedchem.5c02624
Abstract

Recombination Activation Protein 51 (RAD51) is the key recombinase in the homologous recombination (HR) repair pathway. Given its high expression in many cancers and its association with poor prognosis, RAD51 represents a compelling therapeutic target for Cancer treatment. Here, we report the development of first-in-class proteolysis-targeting chimeras (PROTACs) directed to RAD51, based on the RAD51-targeting small-molecule inhibitors RI-1 and RI-2. Among them, SZU305 (15b) showed potent and selective RAD51 degradation and antiproliferative effects in multiple liver Cancer cell lines, inducing near-complete RAD51 depletion in both SK-HEP-1 and Huh-7 Cancer cells. Mechanistically, 15b reduces HR efficiency and impairs DNA damage repair, thereby enhancing chemoradiation sensitivity. In vivo, SZU305 showed strong antitumor activity without apparent toxicity, particularly when combined with sorafenib or irradiation in a Huh-7 xenograft model. These findings highlight the therapeutic potential of RAD51 degradation as a novel strategy to overcome drug resistance in liver Cancer.

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