Proteolysis-Targeting Chimeras: Harnessing the Ubiquitin-Proteasome System to Induce Degradation of Specific Target Proteins

The ubiquitin-proteasome system plays a central role in regulating protein homeostasis in mammalian cells. It is a multistep process involving the polyubiquitination of proteins prior to their proteolytic degradation by the 26S proteasome complex. Blockade of this process results in the accumulation of proteins that are deleterious to the survival of cancer cells and has led to the approval of the proteasome inhibitors bortezomib and carfilzomib for the treatment of multiple myeloma and mantle cell lymphoma. Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules designed to recruit an E3 ubiquitin ligase to a specific target protein, thereby providing a mechanism to ubiquitinate and degrade specific pathological proteins. A significant body of preclinical data, generated since PROTACs were first introduced 15 years ago, demonstrates that PROTACs provide a robust approach to expose new cell biology and to generate novel therapeutics with the potential to target currently undruggable proteins.