ABSTRACT
The success rate of mechanism-based drug discovery depends on the drug targets. With the rapid development of genomics and proteomics, a lot of nonenzymic proteins have been identified as potential drug targets. However, these nonenzymic proteins cannot be regulated by occupying the active site, which were recognized as undruggable targets. Direct regulation of the concentration of these proteins in cells by the innate ubiquitin-proteasome is a potential approach to target these proteins. The ubiquitination of target protein by E3 ligase is the key step for ubiquitin-proteasome mediated protein degradation. Proteolysis targeting chimeras (PROTACs) can facilitate the assembly of complex that consists of the target protein and E3 ligase. The target protein will be ubiquitinated, leading to the degradation by proteasome. This type of regulation mechanism can expand the scope of potential drug targets, and the development of PROTACs may be an innovative strategy in drug discovery.