Protein targeting, PROTAC opens new field of tumor treatment

Protein degradation targeting chimeras (PROTAC) are currently a very hot drug development technology. The structure of PROTAC is like a "dumbbell", connecting the "protein ligand of interest" and the "recruiting ligand of E3 ubiquitin ligase" through a "connector".

The ligand of the protein of interest is a potential cancer-causing target protein, and we hope to remove it; the E3 ubiquitin ligase plays a "labeling" role, and the labeled complex can be degraded by the degradation machinery (proteasome) in our body. PROTAC organically connects the two to help remove target proteins (Figure 1).

Figure 1       Schematic diagram of PROTAC function

Compared with traditional targeted therapies, PROTAC targeted protein technology has many advantages:

 ▶ No need to bind tightly to the target protein, only "labeling" can induce degradation of the target protein; 

▶ Targeting undruggable targets (such as KRAS); 

▶ Can overcome tumor drug resistance; 

▶ Effectively prolongs the action time and has long-lasting curative effect; 

▶ It can not only affect the enzymatic function of the protein, but also regulate its non-enzymatic function.

In addition, PROTAC technology has rich potential targets. A research paper just published in the journal "Cell" shows that PROTAC has 120 potential targets, among which the most commonly degraded proteins are included in important pathways of tumor proliferation such as the cell cycle (Figure 2).

Figure 2      Potential targets of PROTAC (A) and the 20 protein molecules with the highest degradation frequency (B)