Targeted Intracellular Protein Degradation as a Potential Therapeutic Strategy
Here we describe the development of a broadly applicable method for small molecule-mediated post-translational protein degradation known as PROteolysis TArgeting Chimeric molecules (PROTACs). This technique utilizes the Ubiquitin Proteasome System (UPS) that controls protein half-life through targeted degradation. The UPS functions by tagging proteins with a polyubiquitin chain, which facilitates their recognition and subsequent degradation in the 26S proteasome. PROTACs are heterobifunctional molecules that will target a specific protein for degradation via the UPS, by forming a complex between the target protein and an E3 ubiquitin ligase. The PROTAC is comprised of a recognition element for the target, a linker, and a recognition element for an E3 ligase. Following addition to cells, a PROTAC brings the targeted protein and E3 ligase into close physical proximity, facilitating the polyubiquitination of the target, and its subsequent recognition and degradation by the proteasome.
A number of different PROTACs, described herein, have been designed and successfully implemented, with considerable diversity in both the target protein and the E3 ligase component. This method has the potential to be useful as both a tool for understanding the role of specific proteins in cellular pathways, and also as a therapeutic designed to specifically eliminate disease-causing proteins from the cell.