Mechanisms and Design Principles of Proteolysis-Targeting Chimeras and Their Emerging Applications

The ubiquitin-proteasome system (UPS) comprises an important cellular process that regulates protein homeostasis by selectively degrading misfolded or damaged proteins, as well as those with short half-lives. Proteins are targeted for proteasomal degradation via a multistep cascade of E1-E2-E3 enzymes that catalyze the polyubiquitination of substrate proteins, which can be recognized by the proteasome and degraded into smaller peptides. Targeted protein degradation is a technology that takes advantage of the UPS for selectively channeling proteins of interest (POI) for proteasomal degradation using compounds that facilitate the interaction of an E3 ligase with the POI as a neo-substrate. This review focuses on the main principles of designing proteolysis-targeting chimeras (PROTACs). The advantages and limitations of PROTAC use as a research tool in the laboratory or as novel therapeutics in clinical trials are also discussed. Initially described in 2001, PROTACs have since revolutionized the drug discovery field and comprise a novel therapeutic modality that expands the druggable proteome via a unique mechanism of action. More than 30 PROTACs have entered clinical trials, and early clinical success of PROTACs targeting well-characterized disease drivers inspired the field to move toward targeting proteins that were previously considered "undruggable" with conventional drug design, such as transcription factors. Over the last two decades since its discovery, the PROTAC technology has gained tremendous excitement in both basic research and drug discovery and could soon become a key therapeutic modality. PROTACs can potentially make a significant impact on the survival and quality of life of patients suffering from different diseases.