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

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Ring Finger Protein 4 (RNF4) plays a role in cancer progression by ubiquitinating key regulatory proteins.
• RNF4 is a potential therapeutic target for hepatocellular carcinoma (HCC).
• No specific inhibitors for RNF4 have been developed previously.

Purpose of the Study:

• To design and synthesize novel Proteolysis-Targeting Chimeras (PROTACs) to induce the degradation of RNF4.
• To evaluate the efficacy of these PROTACs in degrading RNF4 and inhibiting HCC cell proliferation.
• To assess the therapeutic potential of the lead compound in preclinical HCC models.

Main Methods:

• Design and synthesis of 28 PROTACs targeting RNF4, based on a covalent binder.
• Screening of PROTACs for RNF4 degradation and anti-proliferative activity in HCC cell lines.
• Evaluation of the lead compound (RD12) in a HCC mouse model and mechanistic studies involving the ubiquitin-proteasome system.

Main Results:

• RD12 demonstrated efficient RNF4 degradation and potent anti-proliferative activity in multiple HCC cell lines.
• RD12 exhibited significant anti-tumour activity in a HCC mouse model with no obvious side effects.
• Mechanistic studies confirmed RD12-induced RNF4 degradation via the ubiquitin-proteasome system, leading to DNA damage and apoptosis.

Conclusions:

• RD12 is the first PROTAC developed to target RNF4 for degradation.
• RD12 shows promising therapeutic potential for hepatocellular carcinoma (HCC) treatment.
• Targeting RNF4 for degradation represents a viable strategy for HCC therapy.