Introduction of Targeted Protein Degradation

Targeted protein degradation (TPD) has emerged as a transformative pharmacological modality that redefines the boundaries of drug discovery. Unlike conventional occupancy-driven inhibitors, PROTACs harness the endogenous ubiquitin-proteasome system (UPS) to catalytically eliminate disease-driving proteins, offering advantages in overcoming resistance, disabling scaffolding functions, and sustaining therapeutic responses. The recent FDA approval of Vepdegestrant (ARV-471) marks the entry of PROTAC technology into large-scale clinical translation, underscoring its therapeutic potential. To equip readers with the background necessary to quickly navigate the in-depth discussions that follow, this chapter provides an essential overview of TPD and establishes the conceptual foundation for this volume. It surveys the core chemical mechanisms and biological characteristics of targeted degraders and traces the evolution of degrader design toward historically undruggable targets. By outlining the logical framework and chapter arrangement of this volume, this chapter provides readers with a clear overview of the scope and organization of the subsequent chapters.