Attacking the “undruggable” target: The rise and evolution of targeted protein degradation technologies

Targeted protein degradation has emerged as a powerful therapeutic paradigm that enables the selective elimination of pathogenic proteins and extends the druggable proteome beyond the reach of conventional inhibition-based strategies. Early advances in this field have been driven predominantly by proteasome-dependent approaches, including proteolysis-targeting chimeras and molecular glues, several of which have demonstrated clinical proof of mechanism. More recently, lysosome-based degradation strategies have further expanded the scope of amenable targets to include aggregation-prone proteins, membrane-associated proteins, and extracellular proteins. In this review, we provide a clinically oriented and pathway-integrated overview of targeted protein degradation technologies, systematically comparing proteasome- and lysosome-dependent strategies with respect to mechanism, target scope, and translational readiness. Representative case studies spanning oncology, neurodegenerative, autoimmune, and viral diseases are discussed to highlight both therapeutic potential and current limitations. We further examine key challenges shaping clinical translation, including E3 ligase tissue specificity, pharmacokinetic and delivery constraints, safety considerations, and resistance mechanisms, and outline emerging design paradigms that integrate structural biology and artificial intelligence to guide the development of next-generation degraders.