Bild: pexels.com/Pavel Danilyuk
From inhibition to degradation: How proteolysis-targeting chimeras (PROTACs) are breaking down the barriers of “undruggability” and paving the way for next-generation cancer therapies.
In modern oncology, classic small-molecule inhibitors (SMIs) regularly reach their limits. While conventional inhibitors block the function of a protein by occupying its active site (occupation-based paradigm), research with proteolysis-targeting chimeras (PROTACs) is pursuing a radically new approach: targeted proteosomal degradation. For physicians and researchers, this means access to target proteins that were previously considered “undruggable.”
The mechanism: The ubiquitin-proteasome system as an ally
PROTACs are heterobifunctional molecules that act as a molecular bridge. They consist of three components:
● a ligand that binds specifically to the target protein (protein of interest, POI)
● a ligand that recruits an E3 ubiquitin ligase
● a chemical linker that connects both functional units
The spatial proximity causes the target protein to be ubiquitinated and subsequently degraded by the cellular 26S proteasome. This catalytic mechanism of action enables a single PROTAC molecule to tag numerous target proteins in succession, resulting in high efficiency at lower doses.
Strategic relevance for clinical research
A key advantage over traditional inhibitors is the ability to overcome resistance. Tumor cells often develop mutations in the active site that prevent inhibitors from binding. However, since PROTACs do not necessarily have to bind to the catalytic site but can use any accessible pocket on the protein surface, they open up new therapeutic windows.
Analytical techniques used in PROTAC research include AlphaScreen®, TR-FRET (fluorescence resonance energy transfer), and NanoBRETTM as a luminescence method. Real-time monitoring of the ubiquitin conjugation and deconjugation phases is possible using the UbiReal test principle as a high-throughput screening method.
International research projects and global collaborations
The momentum in PROTAC development is being driven by well-funded international consortia.
Academic-industrial partnerships:
In the US and Asia, heavyweights such as Arvinas, Pfizer, and Roche are collaborating intensively with university hospitals to optimize the pharmacokinetics of the often quite large-molecular chimeras. A particular focus is on overcoming the blood-brain barrier for the treatment of CNS metastases.
EU initiatives:
Projects such as the European Research Council (ERC)-funded project on the “Design and biological evaluation of PROTACs as anti-cancer agents” (H2020) focus on the development of novel E3 ligase ligands beyond Cereblon (CRBN) and VHL.
The breakthrough: Clinical milestones in Phase III
For a long time, PROTAC technology was considered experimental. This has changed fundamentally. We are currently observing the entry of the first candidates into the regulatory trial phases:
Vepdegestrant (ARV-471):
The company Arvina is well advanced in its research into protein degradation therapies. The orally available estrogen receptor (ER) degrader vepdegestrant is currently being investigated in a large-scale Phase III study (VERITAC-2) in patients with ER-positive/HER2-negative locally advanced or metastatic breast cancer. Phase I/II data have already shown a significant reduction in ER levels in tumor tissue and a clinical benefit rate that potentially eclipses conventional fulvestrant therapies.
Bavdegalamide (ARV-110):
The target here is the androgen receptor (AR). Following promising results in patients with metastatic castration-resistant prostate cancer (mCRPC) who had already received multiple prior therapies, the developers are paving the way for broader clinical applications in advanced stages.
Outlook for clinical practice
PROTAC technology is transforming oncology from functional blockade to physical elimination of pathogenic proteins. For the medical profession, this means new treatment options for patients who no longer respond to standard therapies. While we await the final data from the Phase III studies, one thing is already clear: targeted protein degradation will become a cornerstone of personalized cancer therapy.