Expanding the druggable proteome strategies and innovations in targeted protein degradation

Abstract

Targeted Protein Degradation (TPD) emerges as a novel therapeutic strategy that selectively eliminates disease-causing proteins by harnessing endogenous degradation systems, thereby overcoming the limitations of traditional drugs in addressing “undruggable” targets. This review outlines the core molecular mechanisms and primary technical platforms of TPD, including PROTACs, molecular glues (MGs), antibody-degradation conjugates, and emerging autophagy-related strategies (LYTACs, AUTACs, ATTECs, etc.). It systematically summarizes molecular engineering advances such as linker optimization, expansion of E3 ligase resources, and environmentally responsive and multi-modular designs. Furthermore, clinical and translational research cases demonstrate TPD's application potential across oncology, neurodegenerative diseases, cardiovascular disorders, and infectious diseases. Addressing challenges such as suboptimal pharmacokinetics, delivery limitations, potential off-target effects, and industrialization hurdles, we identify critical scientific questions requiring resolution and highlight emerging directions including AI-enabled design, nanomaterial delivery, and interdisciplinary integration. Overall, TPD is propelling drug development from “functional inhibition” toward “protein clearance,” injecting new vitality into precision medicine. This paper aims to provide a systematic reference for subsequent research and clinical translation.