PROTAC Pharmaceutical Research and its Applications

Abstract

At present, there are very few protein targets that can be used as drugs, with approximately 15% of proteins being regulated by small molecules and biomacromolecules, while 85% of proteins currently do not have drug targets and cannot be regulated by small molecules and biomacromolecules. Proteolytic targeting chimeras (protacs) can degrade many non-pharmacological target proteins through proteasomes, thereby regulating their regulatory effects. Protein degradation targeting chimeras is an emerging direction in drug research and development. Traditional inhibitors have a blocking effect, leading to drug resistance and off target phenomena. However, this technology degrades the target protein through a 26S protease system. Structurally, PROTAC consists of three parts: the left end is a ligand that binds to the target protein, the right end is a ligand that connects to ubiquitin ligase, and the middle is connected through a "Linker". In the patient's body, one end of PROTAC is connected to E3 ubiquitin ligase, and the other end is connected to the target protein to be degraded. Through multiple rounds of ubiquitination, a ubiquitin chain is formed, achieving the UPS system to degrade the target protein. PROTAC small molecules have great prospects in the treatment of diseases. Unlike traditional small molecule drugs, they do not destroy the function of proteins, but completely degrade them. And PROTAC can be recycled, and the proteins of interest are polyubiquitinated and degraded through proteasomes. The dissociated PROTAC can also initiate new degradation, which is an important breakthrough in the fight against cancer cells. For example, we can design a PROTAC to hijack the protein required for unlimited proliferation of cancer cells, so that it can be degraded and inhibit the growth of cancer cells. Further exploration is needed for the development and clinical application of PROTAC drugs.