Proteolysis‐Targeting Chimera (PROTAC): A Revolutionary Tool for Chemical Biology Research

Abstract Proteolysis‐targeting chimera (PROTAC) technology is a revolutionary tool for drug discovery that simultaneously recruits E3 ligase and the protein of interest to induce ubiquitination and subsequent proteasomal degradation. Since the inaugural PROTAC prototype emerged in 2001, this modality has garnered significant interest across academia and industry, catalyzing transformative applications in drug discovery and chemical biology. The field has evolved from foundational investigations into molecular design, structural optimization, and protein target extension to address more sophisticated challenges, such as structural analysis of ternary complexes, expansion of diversified therapeutic indications, and clinical translation studies. Recent progress across chemical, pharmaceutical, and biochemical sciences has reshaped PROTAC design paradigms, which in turn expanded the chemical biology toolkit. In this review, pivotal milestones are systematically chronicled in PROTAC development, evaluate emerging strategies for diversifying E3 ligase utilization and expanding the scope of degradable targets, and summarize a series of instrumental and biochemical methodologies that propelled sequential breakthroughs. Additionally, forward‐looking trajectories are proposed to address current limitations and accelerate the clinical maturation of PROTAC‐based therapeutics.