Protein degraders represent an advancement in drug discovery, offering a new approach by eliminating harmful proteins. This new class is exciting for its potential in previously untreatable conditions. Unlike conventional drugs, which often only block protein function, protein degraders remove disease-causing proteins, opening new avenues for treatment.
Understanding Protein Degraders
Protein degraders are molecules hijacking the cell’s waste disposal systems. Instead of inhibiting a problematic protein, they tag it for destruction. Unlike traditional small molecule inhibitors that block a protein’s active site, halting its function, degraders remove it.
Protein degraders leverage the cell’s protein turnover machinery. Cells constantly produce and break down proteins. Protein degraders exploit this system to eliminate specific disease proteins. This expands treatable targets, including many “undruggable” proteins.
The Mechanism of Action
Protein degraders engage the ubiquitin-proteasome system (UPS), the cell’s degradation pathway. This system uses ubiquitin, a small protein tag, to mark proteins. Once tagged, a protein is dismantled by the proteasome.
These degraders act as “molecular matchmakers” or “molecular glues.” PROteolysis TArgeting Chimeras (PROTACs) are common bifunctional molecules with two linked parts. One part binds to the target protein, the other to an E3 ubiquitin ligase. This brings the target protein and E3 ligase together, forming a “ternary complex.” The E3 ligase tags the protein with ubiquitin for degradation.
Beyond Traditional Drugs
Protein degraders offer advantages over conventional drugs. Their catalytic nature means a single degrader can destroy multiple target protein copies. This allows lower concentrations, reducing side effects and requiring less frequent dosing than inhibitors that must constantly occupy a target.
Protein degraders can also target “undruggable” proteins. Many disease proteins lack a suitable binding pocket for traditional inhibitors, making them inaccessible. Degraders do not require an active site; they bind to the target protein to bring it to the degradation machinery. This expands the therapeutic landscape to proteins like scaffolding or transcription factors. Degraders can also overcome drug resistance from mutations or target protein overexpression, as degradation eliminates the protein.
Therapeutic Applications
Protein degraders are investigated across therapeutic areas where traditional approaches have faced limitations. Oncology is a primary focus, with many degraders in clinical trials for cancers. By eliminating oncogenic proteins, they stop cancer growth. For example, degraders targeting the estrogen receptor (ER) and androgen receptor (AR) are developed for breast and prostate cancers.
Neurodegenerative diseases, like Alzheimer’s and Parkinson’s, are a significant research area. In these conditions, misfolded or aggregated proteins accumulate, contributing to disease. Protein degraders clear these toxic aggregates, addressing underlying causes. They are also explored in autoimmune and inflammatory conditions.
The Road Ahead
Protein degrader research is advancing, with many compounds in preclinical and clinical development. As of mid-2025, over 30 protein degrader candidates are in human clinical trials, primarily for cancer. Some have progressed to Phase 3 trials, targeting the estrogen receptor, androgen receptor, and Bruton’s tyrosine kinase.
Prospects are promising, but challenges remain in optimizing these molecules, including solubility, cell permeability, and off-target effects. Researchers are also exploring novel degrader types, such as molecular glues, which are smaller and promote protein interactions for degradation. Despite these complexities, protein degraders’ ability to address previously untreatable targets represents a step forward with potential to transform medicine.