Proteolysis targeting chimeras for drug discovery from mechanistic basis to clinical translation

Abstract

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional small molecules that induce selective degradation of disease-associated proteins through the ubiquitin-proteasome system. Rather than transiently inhibiting protein function, PROTACs induce selective elimination of the target protein. This event-driven pharmacological strategy offers significant advantages for targeting proteins that are difficult to modulate using conventional occupancy-driven inhibitors. Since the initial proof-of-concept studies and the entry of the first PROTAC candidates into clinical trials, targeted protein degradation has evolved into a clinically relevant therapeutic platform, particularly in oncology. In this review, we examine how these degraders work and the chemistry involved in their design—from linker optimization to selecting E3 ligases. We also explain how they form the molecular connections needed to function. Representative clinical programs targeting the androgen receptor, estrogen receptor, bromodomain-containing proteins, and Bruton tyrosine kinase are discussed to illustrate current therapeutic progress, remaining challenges, and lessons learned during clinical development. We also explore the hurdles in bringing these to patients, such as large molecular size, solubility, limited cell permeability, pharmacokinetics, tumor resistance, and the complexity of manufacturing. Emerging approaches, including reversible degraders, photoactivatable PROTACs, antibody-directed delivery systems, and artificial intelligence-assisted molecular design, are also highlighted as promising strategies to improve selectivity and drug-like properties. Collectively, these advances establish PROTAC technology as a transformative platform in modern drug discovery while emphasizing the scientific and translational challenges that must be addressed to enable broader clinical application.