What is PROTAC

What is PROTAC?

PROTAC is an abbreviation of Proteolysis Targeting Chimera, and a protein degradation-targeting chimera. It is a small bifunctional molecule. One end is a ligand that binds the target protein and the other end is a ligand that binds E3 ubiquitin ligase. The target protein and the E3 enzyme can be drawn close in the body so that the target protein is labeled with ubiquitin and then degraded by the ubiquitin-proteasome pathway.

What are the characteristics and advantages of PROTAC?

PROTAC  is "Event driven", not "occupancy driven";

Both small molecule inhibitors and macromolecular antibodies need to continuously occupy the active site of the target protein to block the function. They are "occupancy driven". (This requires the drug to meet: a large dose to saturate the target; a long half-life to sustain inhibition; a high affinity to "grab the original ligand / receptor)". This will cause many problems, for example, if the dose is large, the toxic and side effects are also large; if the affinity is too high, it may easily lead to off-target toxicity; the target is mutated / overexpressed and drug resistance occurs.)

PROTAC only provides binding activity, triggering the event that the target protein binds to the E3 enzyme to trigger degradation, which is "event driven". It does not need to directly inhibit the functional activity of the target protein, and the drug does not need to interact with the target protein for a long time. High-strength binding makes it possible to target traditional undruggable targets.

Advantages:

1. The doseis small, and the amount of catalyst is sufficient.


2. Low toxicity.


3. Overcoming resistance caused by mutation / overexpression of target protein.


4. It does not depend on affinity and can be highly selective.


5. Remove protein buildup.

What are the technical disadvantages of PROTAC?

These drugs are dual-target drugs, so molecular weight, molecular rigidity, and water solubility are not ideal, so oral absorption and membrane permeability are poor. PROTAC molecules are usually large, and the PK is a major obstacle.

Off-target toxicity should also be one of the most worrying issues. Traditionally, small molecules, macromolecular drugs, and even small nucleotides that target protein activity generally do not inhibit protein activity too much, and do not affect the expression of backbone proteins. While at the same time, the residual activity may also guarantee the basic physiological activities of normal cells, tissues and organs, and reduce potential toxicity. As a more thorough target degrader, even if the target has been previously verified, it will bring more serious toxicity, which needs to be closely monitored in future clinical experiments.

Another challenge is that the off-target effect of degradation is not easy to detect and track in the preclinical toxicity screening, which increases the risk in the later development of the drug.

In addition, this technique is obviously only effective for proteins that need to be inhibited, but it is not useful for discovering agonists.

What are the future direction of PROTAC?

Because PROTAC only provides binding activity, triggering the target protein to bind to the E3 enzyme and trigger degradation, so for those unknown targets or targets that are difficult to target, based on the DNA-encoded compound library can be the best starting point for finding protein degradation agents. But drugs such as PROTAC are dual-target drugs, except for molecular weight, molecular rigidity, and water solubility. Even more important is the need to figure out whether proteins should be degraded. Artificial intelligence analysis tools may be able to determine which targets are most likely to treat disease without dangerous side effects.