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

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.