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

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.