A Review of Proteolytic Targeting Chimeras

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The concept of proteolytic targeting chimera (PROTAC) was first proposed by Crews and Deshaies laboratory in 2001, the team successfully achieved the degradation of methionyl aminopeptidase 2 (MetAp-2) by PROTAC method. Since then, PROTACs targeting androgen receptor (AR) and estrogen receptor (ER) have appeared one after another. In 2004, a PROTAC molecule that recruited the tumor suppressor protein VHL through a polypeptide fragment on HIF1-α showed a greater improvement in membrane permeability and could also exist stably in cells. However, these peptide-based PROTAC molecules were not ready for drug preparation.

Until 2008, when the first small-molecule E3 ubiquitinase ligand-based PROTAC came out, marking the beginning of small-molecule PROTAC research, and PROTAC research also entered the development stage. In the following years, several important small molecule ligands, including VHL ligands, were successively developed, and corresponding PROTACs were also successfully synthesized. After that, CLIPTAC molecules (clickformed proteolysis targeting chimeras) generated by self-assembly in cells through “click technology” and halogenated PROTACs (haloPROTACs) appeared one after another, and the research on PROTACs also became more and more in-depth and entered the molecular level.

PROTAC is a bifunctional molecule composed of three parts: one end is the target protein binding ligand, the other end is the E3 ubiquitin ligase ligand, and the middle is the linker chain. In cells, PROTAC molecules can recognize and selectively bind target proteins, recruit specific E3 ubiquitin ligases, and form a “target protein-PROTAC-E3 ubiquitin ligase” ternary complex. Afterwards, E3 ubiquitin ligase and E2 ubiquitin conjugating enzyme work together to ubiquitinate the target protein. Since the ubiquitin-proteasome system (UPS) is an important pathway for protein degradation in human cells, it is involved in the degradation of more than 80% of proteins in cells. Therefore, after the target protein is ubiquitinated, the PROTAC molecule interacts with the target protein and E3 ubiquitinase. Once isolated, the ubiquitin-tagged target protein is recognized and degraded by the proteasome.

By relying on the physiological process of ubiquitination-degradation proteins existing in the human body, PROTAC molecules can efficiently and specifically catalyze the degradation of pathogenic proteins, so as to achieve the purpose of treating diseases. Unlike traditional protein small molecule inhibitors, the mechanism of action of PROTAC is event-driven and does not require prolonged occupation of the target. After PROTAC completes the ubiquitination labeling of a target protein, it can be separated from the target protein and E3 ubiquitin ligase and continue to label the next protein.

Therefore, in the process of exerting the degradation effect, a small amount of PROTAC molecules can achieve the purpose of inducing degradation of a large number of target proteins. In addition, PROTAC can generate selectivity for different kinds of target proteins and E3 enzymes, and the openness of its molecular design further improves the selectivity of PROTAC for target protein degradation. More importantly, compared with kinase inhibitors, PROTAC molecules have lower requirements for the affinity of target proteins. By rationally designing the molecular structure of PROTAC, it has a wide range of applications in targeting some currently undruggable targets.

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