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| What is PROTAC and how do they treat diseases? |
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Approximately 80% of pathogenic proteins, including many key drivers of cancer and other serious neurological diseases such as Alzheimer's disease, currently available treatment methods cannot target them. These so-called "untreatable" proteins lack specific surface areas required for treatment, such as small molecule inhibitors or antibodies that bind to disease-causing proteins and regulate their function.
However, an alternative therapeutic strategy called targeted protein degradation has shown the potential to repair these "untreatable" proteins. This strategy utilizes small molecules called PROTAC to promote the destruction of pathogenic proteins through the cell's waste disposal system. Dr. Eric Fisher. The assistant professor of biochemistry and molecular pharmacology at Harvard Medical School recently sat down with us to help write this introductory book on PROTAC and its potential impact on treating diseases.
What is PROTAC?
Protein hydrolysis targeting chimeras, also known as PROTACS, are two separate molecules that combine to form a bipartite molecule. One end binds to ubiquitin ligase, while the other end binds to the "non producible" protein targeted by pharmacologists. In the illustration, PROTAC is often depicted as dumbbells, but treating them as flexible seat belts may be more helpful.
How does PROTAC work?
PROTAC aims to use the cell's waste treatment system to remove unwanted proteins. This system is called proteasome, which is crucial for cells to remove unwanted or damaged proteins and recover their building blocks to manufacture new proteins. Proteasomes play a crucial role in cell growth, cell stress management, and the immune system. One end binds to the target protein, while the other end of the molecule binds to ubiquitin ligase, which then labels the target protein for destruction. This allows the cell's proteasome to know that this specific protein can be disrupted. In this way, the regular mechanisms of the body are collectively selected to disrupt the proteins that cause diseases.
What makes PROTAC so unique?
Most therapies are divided into small molecule inhibitors or therapeutic antibodies/biologics. However, "PROTACs are small molecules, so they are not limited to targeting surface proteins. However, compared to traditional small molecule inhibitors, PROTACs have fundamental differences," Dr. Fischer explained. "Although inhibitors need to achieve almost perfect targeting for a long time to fully exert their pharmacological effects, PROTACs follow more hit and run strategies." "Optimized degradation molecules will have rapid degradation and relatively short therapeutic dose exposure time, completely eliminating the target protein, which can produce more lasting and in-depth effects," he explained. "However, more importantly, small molecule degrading agents completely eliminate pathogenic proteins, allowing them to target the non catalytic activity of enzymes as well as scaffold proteins and other non enzymatic targets."
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