Abstract
Proteolysis targeting chimeras (PROTAC) represents a new type of small molecule induced protein degradation technology that has emerged in recent years. PROTAC uses bifunctional small molecules to induce ubiquitination of target proteins and utilizes intracellular proteasomes for chemical knockdown. It complements the gene editing and RNA interference for protein knockdown. Compared with small molecule inhibitors, PROTAC has shown great advantages in overcoming tumor resistance, affecting the non-enzymatic function of target proteins, degrading undruggable targets, and providing new rapid and reversible chemical knockout tools. At the same time, its challenges and problems also need to be resolved as a fast-developing newchemical biology technology.
Highlights
In recent years, targeted protein degradation has attracted much attention from the pharmaceutical industry, among which the focus is undoubtedly the proteolysis targeting chimeras (PROTAC) technology induced by small molecules
We have analyzed the related PROTACs that have been reported to illustrate their advantages from different perspectives
Due to the large number of targets and the complex structure of the PROTACs, 51 of them mentioned in this review have been summarized and analyzed
Summary
In recent years, targeted protein degradation has attracted much attention from the pharmaceutical industry, among which the focus is undoubtedly the proteolysis targeting chimeras (PROTAC) technology induced by small molecules. PROTAC is a new technology that uses small molecules to induce degradation of target proteins to regulate the protein level. The ubiquitin-proteasome system in cell (Amm et al, 2014) plays an important role in the process of protein degradation. PROTACs mainly play a related role in the first stage in the process of inducing protein degradation. PROTACs induce the target protein and E3 ubiquitin ligase to form a ternary complex by utilizing a bifunctional small molecule, which can simultaneously bind the target protein and E3 ubiquitin ligase. The complex makes the target protein recognized by E3 ubiquitin ligase and ubiquitinated, recognized and degraded by the proteasome in cells (Figure 1). Having the advantages of high precision and strong versatility, it cannot dynamically regulate the target
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