PROTACs: the game-changing technology that promises to tackle “undruggable” proteins

Almost all pharmaceutical drugs today act by binding to disease-causing proteins and inhibiting their activity. Unfortunately, there are still many target proteins — as much as 85% of the human proteome by some estimates — that lack active sites or well-defined pockets where drugs can bind, hindering their use as effective therapeutics.

Today, however, a new class of molecules known as proteolysis targeting chimeras, or PROTACs for short, has the potential to tackle those once considered “undruggable” targets. In contrast to small molecule drugs, which work by binding to a specific site and blocking the function of a target protein, PROTACs bind to any site within the protein’s structure and are designed to perform quite a different job: to destroy and eliminate their target for good.

But how can PROTACs do this? Let’s find out.

 

How do PROTACs work?

PROTACs are small molecules that are made up of two “heads” joined together by a linker. One of them binds to a disease-causing protein, while the other one binds to an ubiquitin ligase — part of the cell’s own protein destruction system that labels damaged and unwanted proteins by adding small protein called ubiquitin onto them. Ubiquitin act as “the kiss of death”— a flag that instructs the proteasome — think of it as a molecular shredder that destroys the flagged proteins. Therefore, by bringing the ligase and the target protein in close proximity, a PROTAC ensures that the target gets marked for destruction.

 

What are the benefits behind the PROTACs strategy?

1. They can bind to virtually any region of a target protein as long as the ubiquitin ligase can access the PROTAC. This greatly expands the drug target space.

2. PROTACs are recycled so smaller amounts of drugs are needed. After target-protein destruction, the PROTAC is released and ready to do its job all over again. This gives PROTACs the advantage to act effectively at lower doses, which translates into better specificity and reduced toxic side effects.

3. It’s a platform or target agnostic technology, therefore it can be applied to many different types of diseases.

Despite the potential of this new therapeutic strategy, the major challenge will be the identification of suitable ligands for current undruggable proteins. Researchers are currently using high-throughput affinity-based screening of small molecule libraries to extend the repository of PROTACs.

While it’s too soon to foresee an end to every disease, PROTACs will likely expand drug development in many currently untreated diseases. For now, all eyes are directed towards the frontrunner PROTACs that are now under clinical trial, led by candidates for prostate and breast cancer.

Learn how Dianthus can help with affinity-based screening in your PROTAC projects.