Almost all current pharmaceutical drugs in the market 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 inhibitor drugs, which work by binding to a specific site and blocking the function of a protein of interest (POI), PROTACs bind to any accessible site within the protein’s structure and perform quite a different job: they destroy and eliminate the the POI for good.
But how can PROTACs do this? Let’s find out.
PROTACs are heterobifunctional molecules that are made up of two ligands joined by a linker — the protein ligand, or “warhead” that binds to a disease-causing protein, and the “anchor” ligand that binds to the substrate binding domain of an E3 ubiquitin ligase. A linker keeps these two components together — its length and composition determine physicochemical properties and bioactivity of the PROTAC.
Once the PROTAC brings the POI and the ligase in close proximity, what happens next is part of the cell’s own protein destruction system. A small protein called ubiquitin is added to damaged and unwanted proteins. The ubiquitin acts as “the kiss of death” — a flag that instructs the ubiquitin-proteasome system, a molecular shredder, to degrade the ubiquitinated proteins. Therefore, by bringing the ligase and the POI in close proximity, a PROTAC ensures it gets marked for destruction.
1. PROTACs can bind to virtually any region of the protein targeted as long as the ubiquitin ligase can access the PROTAC. This greatly expands the drug target space beyond the active site.
2. PROTACs are recycled so smaller amounts of drugs are needed. After the POI is degraded, the PROTAC is released and ready to do its job all over again. This event-driven mode of action gives PROTACs the advantage to act effectively at lower doses compared to doses of small molecule inhibitors, which have an occupancy-driven mode of action that requires higher dosages to ensure full occupancy to effectively inhibit the POI. Lower dosage 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, although the main focus has been to utilize this modality for cancer and neurodegenerative diseases.
Despite the potential of this new therapeutic strategy, one of the challenges is the identification of suitable ligands for current undruggable proteins. Researchers are currently using biophysical methods to conduct 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 under clinical trial, led by candidates for prostate and breast cancer. Learn about the progress some candidates are making.
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