PROTACs

PROteolysis-TArgeting Chimeras (PROTACs) exploit the intracellular ubiquitin-proteasome system to selectively degrade target proteins. Recently, small-molecule PROTACs with high potency have been frequently reported.  The emerging characteristics of small-molecule PROTACs, such as inducing a rapid, profound and sustained degradation, inducing a robust inhibition of downstream signals, displaying enhanced target selectivity, and overcoming resistance to small molecule inhibitors. In tumor xenografts, small-molecule PROTACs can significantly attenuate tumor progression. The outstanding advantages over traditional small-molecule drugs and the promising preclinical data suggest that small-molecule PROTAC technology has the potential to greatly promote the development of targeted therapy drugs.
PROTACs are designed to take advantage of the cell’s waste disposal system that removes unneeded proteins. This system, known as the proteasome, is important for the cell to remove unneeded or damaged proteins and recycle their building blocks to make new proteins. The proteasome plays critical roles in cell growth, management of cellular stress, and in the immune system. One end binds to the targeted proteins, while the other end of the molecule binds to the ubiquitin ligase, which then marks the targeted protein for destruction. This lets the cell’s proteasome know that this specific protein can be destroyed. In this way the body’s regularly occurring mechanisms are co-opted to destroy disease-causing proteins.