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

Jinbo Huang1,2,3, Haiyu Wang1,2,3, Daohong Jiang1,2,3

  • 1Institute 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.

Journal of Medicinal Chemistry
|February 10, 2026
PubMed

Insights

Researchers developed novel PROTACs targeting RAD51, a key protein in DNA repair. One compound, SZU305, effectively degraded RAD51 in liver cancer cells, showing promise for overcoming drug resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Recombination Activation Protein 51 (RAD51) is crucial for homologous recombination DNA repair.
  • High RAD51 expression correlates with poor prognosis in various cancers, making it a therapeutic target.

Purpose of the Study:

  • To develop first-in-class proteolysis-targeting chimeras (PROTACs) specifically targeting RAD51.
  • To evaluate the efficacy of these RAD51-targeting PROTACs in liver cancer models.

Main Methods:

  • Development of RAD51-targeting PROTACs based on RI-1 and RI-2 inhibitors.
  • Assessment of RAD51 degradation and antiproliferative effects in liver cancer cell lines (SK-HEP-1, Huh-7).
  • Evaluation of in vivo antitumor activity and toxicity in a Huh-7 xenograft model, including combination therapies.

Main Results:

  • SZU305 (15b) demonstrated potent and selective RAD51 degradation in liver cancer cells.
  • SZU305 reduced homologous recombination efficiency, impaired DNA repair, and enhanced chemoradiation sensitivity.
  • In vivo studies showed strong antitumor activity of SZU305, especially combined with sorafenib or irradiation, with no apparent toxicity.

Conclusions:

  • RAD51 degradation via PROTACs is a promising therapeutic strategy for liver cancer.
  • SZU305 represents a potential novel agent to overcome drug resistance in liver cancer treatment.

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