Chemistries of bifunctional PROTAC degraders

Proteolysis targeting chimeras (PROTACs) technology is a novel and promising therapeutic strategy using small molecules to induce ubiquitin-dependent degradation of proteins. It has received extensive attention from both academia and industry as it can potentially access previously inaccessible targets. However, the design and optimization of PROTACs present big challenges for researchers, and the general strategy for its development and optimization is a lot of trial and error based on experience. This review highlights the important advances in this rapidly growing field and critical limitations of the traditional trial-and-error approach to developing PROTACs by analyzing numerous representative examples of PROTACs development. We summarize and analyze the general principles and strategies for PROTACs design and optimization from the perspective of chemical structure design, and propose potential future pathways to facilitate the development of PROTACs.