Targeted Protein Degraders

Targeted protein degradation based on proteolysis-targeting chimeras (PROTACs) is a rapidly advancing strategy for modulating protein function through their selective removal via the ubiquitin–proteasome system. PROTACs are hetero-bifunctional small molecules that simultaneously engage a protein of interest and an E3 ubiquitin ligase, promoting the formation of a ternary complex that triggers ubiquitination and subsequent degradation. Unlike classical occupancy-driven inhibitors, PROTACs operate catalytically and can eliminate rather than merely block their targets, thereby extending therapeutic possibilities to proteins that are difficult to modulate using conventional medicinal chemistry approaches.

By leveraging this event-driven mechanism, PROTAC technology has opened new avenues for addressing biological targets previously considered undruggable, broadening the conceptual space for therapeutic intervention across a wide range of diseases.

In the context of liver pathophysiology, growing evidence suggests that specific molecular regulators contribute to the transition from early metabolic dysfunction to advanced inflammatory and oncogenic stages. Within this framework, PROTAC-mediated degradation represents a promising and conceptually powerful approach to interfere with pathological drivers involved in disease initiation and progression, potentially offering new opportunities for intervention in conditions that culminate in liver malignancies.