Pharmacist Manfred Schubert-Zsilavecz explains the new active substances.
Until now, almost all medications have influenced disease processes by either replacing missing molecules or blocking malfunctioning molecules (or their production). A new type of active substance, called “Proteolysis Targeting Chimera” or PROTACs, takes a different approach: they use the cell’s own “waste shredders” to eliminate disruptive proteins. None of these substances have been approved yet, but a short while ago, an admissions application was submitted for Vebdegestrant (see below).
The Challenge
In many diseases, cells in the body produce far too much of a protein or produce it at the wrong time. Sometimes, harmful proteins are even produced that shouldn’t exist at all. Treatments often involve medications that block either the relevant protein itself or its production.
Two examples:
- Many people produce too much cholesterol in their bodies. Statins are drugs that lower a key enzyme in the liver responsible for cholesterol biosynthesis, thereby reducing the body’s cholesterol production.
- Headaches: Many headaches begin with the formation of certain pain substances by two enzymes called Cox1 and Cox2. Ibuprofen, aspirin, diclofenac, and naproxen block these enzymes, preventing pain from occurring.
Over 20 years ago, scientists – including this year’s endowed visiting professor – came up with a completely new idea: Every cell, they reasoned, has a protein shredder for waste. The question was: Could this shredder be directed to target the relevant enzyme or receptor, essentially breaking it down into tiny pieces? As it turns out, this is possible. The first drugs that work this way are currently being tested in clinical trials. They are called PROTACs, or “Proteolysis Targeting Chimeras.”
How the shredder knows what to shred
The protein shredder in cells doesn’t just break down everything it encounters. It only shreds a protein if a kind of cellular “labeling machine” has first attached a label saying “ready to go.” The official name of this machine is Ligase E3. PROTACs need to bring the unwanted proteins together with this machine. To achieve this, researchers in pharmaceutical labs have developed compounds made of two parts: while one part is designed to bind to the “labeling machine,” the other is built to attach to the unwanted protein. When such medication is administered to a person, these dual molecules enter the cells and connect with the machine and the target protein. The machine labels the target protein, and the shredder takes care of the rest.
Diseases where PROTACs could help
Many companies are undertaking efforts to develop new treatment options for patients with a wide range of illnesses. For cancer alone, more than 70 different PROTACs are in development, targeting breast cancer, prostate cancer, lung cancer, lymphoma, and other types of the disease. But the focus isn’t just on cancer – autoimmune diseases like rheumatoid arthritis or atopic dermatitis are also being addressed. These conditions require suppression of immune responses. While conventional medications already work well for many patients, they don’t help everyone. In laboratories, researchers are experimenting to see if PROTACs could also be used to combat viruses, which – aided by viral proteins – invade cells and replicate within them. PROTACs could potentially ensure that these viral proteins are quickly eliminated. Another exciting field is neurodegenerative diseases, which often involve proteins that clump together and accumulate as waste in nerve cells. In Alzheimer’s disease, these consist of aggregates of tau protein, which are also involved in frontotemporal dementia. In Parkinson’s disease, alpha-synuclein aggregates play a role, while the same is true of aggregates of mutated huntingtin protein in Huntington’s disease. There are currently no approved medications to prevent these protein aggregations. Some companies are now working to develop PROTACs to target these aggregates. If the aggregation itself can’t be prevented, the goal is to shred the aggregates afterward. However, these PROTACs are still in the laboratory stage.
Admissions application for Vepdegestrant submitted to the FDA
On August 8, 2025, pharmaceutical companies Arvinas and Pfizer announced that they had submitted an admissions application to the FDA for the jointly developed protein degrader Vepdegestrant (1). This application is significant as it marks a milestone in the development of PROTACs, which have not been therapeutically available outside of clinical trials until now. PROTACs are orally administered bifunctional agents that induce the targeted degradation of disease-related proteins within cells. Vepdegestrant binds to the estrogen receptor (ER) with an estrogen-mimetic molecular component and to the E3 ligase with another molecular component. This induced proximity between the ER and E3 ligase leads to ubiquitinylation and, subsequently, the targeted degradation of the estrogen receptor protein by the cellular proteasome. Vepdegestrant is expected to be approved in 2026 for the treatment of patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) and ESR1-mutated breast cancer who have previously undergone endocrine therapy.
Prof. Dr. Manfred Schubert-Zsilavecz serves as Chair of the Board of Trustees for the Friedrich Merz Visiting Fellowship Endowment.
PROTAC
The name PROTAC stands for “Proteolysis Targeting Chimera.” This agent is called a chimera because it consists of two completely different parts – similar to how the mythical chimera was composed of multiple animals. “Targeting” refers to aiming at something, while “Proteolysis” is the scientific term for breaking down proteins. PROTACs, therefore, are chimeras designed to specifically target and break down proteins.
