Protein degraders are a class of molecules developed to pinpoint and eliminate specific, unwanted proteins within cells. This method, known as targeted protein degradation (TPD), is distinct from traditional drugs that only inhibit a protein’s function. Instead, these molecules harness the body’s cellular processes to remove a target protein entirely.
This approach offers a new strategy for addressing the molecular basis of various diseases. By removing disease-causing proteins rather than just blocking them, degraders open new possibilities for both treatment and research.
The Cellular Machinery Behind Degraders
Our cells operate a quality control system to dispose of old, damaged, or unneeded proteins, a process that maintains cellular health, or homeostasis. The primary mechanism is the ubiquitin-proteasome system (UPS), which identifies and breaks down specific proteins.
The process begins when molecules of a small protein called ubiquitin are attached to a target protein, tagging it for destruction. This tagging involves a series of enzymes, with E3 ubiquitin ligases providing specificity by transferring ubiquitin to the designated protein.
Once tagged with a chain of ubiquitin, the protein is recognized by a large complex called the proteasome. The proteasome acts like a molecular shredder, unfolding the protein and cutting it into small fragments. Protein degrader technologies leverage this natural disposal system, redirecting it to eliminate disease-causing proteins.
Prominent Degrader Technologies
Among the leading degrader technologies are Proteolysis-Targeting Chimeras (PROTACs). These are bifunctional molecules with two distinct ends connected by a chemical linker. One end is designed to bind to the specific protein targeted for removal, while the other end recruits an E3 ubiquitin ligase. This action brings the target protein and the cell’s tagging machinery into close proximity.
This induced proximity facilitates the transfer of ubiquitin from the E3 ligase to the target protein, marking it for degradation by the proteasome. Another class of degraders is molecular glues. These smaller molecules work by changing the surface of an E3 ligase, inducing it to recognize and bind to a protein that it would not normally interact with. This newly formed interaction also leads to ubiquitination and degradation.
While PROTACs and molecular glues use the proteasome, other technologies are emerging. Lysosome-Targeting Chimeras (LYTACs), for example, are designed to eliminate proteins on the cell surface or outside the cell. They work by linking a target protein to receptors that trigger endocytosis, delivering the unwanted protein to the lysosome for breakdown.
Degraders as Therapeutic Agents
The application of protein degraders is generating interest in the development of new medicines for diseases driven by harmful proteins. In oncology, this technology offers a way to target cancer-promoting proteins that have been difficult for traditional drugs to inhibit. Many of these “undruggable” targets lack the well-defined active sites that conventional inhibitor drugs require, a limitation that degraders can overcome.
Degraders present several advantages over standard inhibitors. Their catalytic nature means a single degrader molecule can cause the destruction of multiple target protein molecules, leading to a sustained therapeutic effect at lower doses. This could also reduce the risk of toxic side effects and drug resistance.
Beyond cancer, research is exploring the use of degraders to clear toxic protein aggregates associated with neurodegenerative conditions like Alzheimer’s and Parkinson’s diseases. A growing number of protein degrader candidates are advancing into clinical trials for various conditions, including cancers and autoimmune disorders. This new modality may offer effective treatments where few options currently exist.
Degraders as Research Tools
Beyond their therapeutic potential, protein degraders serve as tools in biological research. Scientists use them to perform “chemical knockdown,” a method for rapidly and selectively removing a specific protein from cells or organisms. This allows for investigation into a protein’s function by observing the consequences of its absence.
This approach offers advantages over genetic methods like RNA interference (RNAi) or CRISPR-based gene editing. While genetic tools target the gene or its messenger RNA transcript, degraders act directly on the protein itself. This direct action results in a faster depletion of the target protein, providing clearer insights into its immediate roles.
This capability is also valuable in the early stages of drug discovery. Researchers can use degraders to validate a drug target by assessing whether its removal produces the desired biological effect. This helps confirm that a protein is a driver of disease before committing resources to a full drug development campaign.