Through PROTAC technology, it is possible to develop drugs against undruggable or difficult-to-drug targets of traditional inhibitors. The PROTAC does not rely on the active site of the target or specific protein-protein interaction to play a role but directly degrades the target, and does not need to have a high affinity with the target to degrade.
The accumulation of target protein can be avoided. PORTAC can efficiently degrade proteins to avoid drug resistance caused by overexpression of target proteins.
Avoid drug resistance caused by target protein mutations. PROTAC can play a role only by binding to or even near the target protein, so some amino acid mutations of the target rarely affect the outcome.
PROTAC has better targeting ability, which can be achieved not only by well-designed POI ligand parts, but also by some E3 ligase ligases specifically expressed in cells or tissues, possessing one more targeting mechanism than traditional drugs.
Low doses work. Because the mechanism ofPROTAC is similar to the catalyst in chemical reaction, the target is degraded without being consumed, so a small dose can play a role, which also avoids the off-target toxicity caused by high-dose drugs.
It has an event-driven pharmacological mechanism with a longer effective period. The amount of PROTACs does not need to be maintained above the so-called effective level all the time. Even a higher affinity ligand in vivo of the target will not affect its degradation by PROTAC.
Disadvantages of PROTAC technology
PROTAC-based drugs are double-target drugs without ideal molecular weight, molecular rigidity, and water solubility, so their oral absorption and transmembrane properties are poor. PROTAC molecules are usually very large, making pharmacokinetics (PK) a major obstacle. Although there have been reports of active PROTAC compounds in vivo that will enter human clinical research this year, overall, PK is still the main obstacle to most PROTAC small molecule proprietary drugs.
The chemical synthesis of PROTAC is much more difficult, and the activity of ternary complex is difficult to regulate. In the process of target protein degradation induced by PROTAC, the formation of “target protein-PROTAC-E3 ubiquitin ligase” ternary complex, as a core biological event, is a necessary step in the multi-ubiquitin modification of target protein. For the degradation efficiency induced by PROTAC, the stability of forming ternary complex is much stronger than PROTAC binding to target protein or E3 ubiquitin enzyme.
Off-target toxicity is also one of the most worrying issues. Traditional small molecules and macromolecular drugs and even small nucleotides that target protein activity generally do not completely inhibit protein activity and do not affect the expression of cytoskeleton proteins, which increases the probability of drug resistance, but meanwhile, the residual activity may also ensure the basic physiological activity of normal cells, tissues, and organs, reducing the potential toxicity. As a more thorough target protein degradation agent, PROTAC may accidentally damage other off-target proteins. Even whether the previously verified targets will bring more serious toxicity need to be closely monitored in future clinical trials.
Another hidden danger is that the off-target effect is hard to detect and track in preclinical toxicity screening, which increases the risk in the later development of drugs. In addition, PROTAC technology is obviously only effective for proteins that need to be inhibited, but is of no use for the agonists.
As the R&D and testing of small molecular degradants are costly, the target proteins are quite limited, which cannot meet the needs of specific protein expression areas.
Most of the existing targeted protein degradation technologies are based on the intracellular ubiquitin-proteasome pathway that mainly acts on intracellular proteins, so the degradation of membrane proteins and secretory proteins is still unsolved at present.
The binding of PROTAC to target protein and E3 ligase is still empirical and lacks the corresponding theoretical basis.
The extent to which the target protein is degraded can trigger the phenotypic response and the immune resistance caused by PROTAC treatment remains to be further studied.
