Traditional drug discovery often focuses on inhibiting disease-causing proteins by blocking their activity. While successful, this approach has limitations when proteins lack suitable binding pockets or develop resistance.
Proteolysis-Targeting Chimeras, or PROTACs, offer a new therapeutic approach. Instead of blocking protein function, PROTACs eliminate unwanted proteins entirely by leveraging the cell’s natural waste disposal machinery. This technology opens new avenues for addressing previously challenging therapeutic targets, often called “undruggable” proteins.
The Molecular Mechanism of PROTACs
PROTACs orchestrate the destruction of specific proteins within the cell. These bifunctional molecules have two active components connected by a chemical linker. One end binds to the protein of interest (POI), the target protein for degradation.
The other end binds to an E3 ubiquitin ligase, an enzyme central to the cell’s protein degradation pathway. A PROTAC brings the POI and E3 ligase into close proximity, forming a three-part ternary complex.
Within this complex, the E3 ligase transfers ubiquitin tags onto the target protein. This process, called ubiquitination, involves attaching multiple ubiquitin molecules to the POI, forming a polyubiquitin chain. These ubiquitin tags signal the protein for destruction.
Once ubiquitinated, the tagged protein is recognized by the proteasome, the cell’s primary protein recycling machinery. The proteasome then unfolds and breaks down the ubiquitinated protein into smaller peptides, removing it from the cell. The PROTAC molecule is not consumed; it dissociates and facilitates the degradation of more target protein molecules.
E3 ubiquitin ligases are crucial for this process, as they provide the specificity for which proteins get ubiquitinated. Over 600 E3 ligases exist in the human body, each recognizing different proteins. In PROTAC development, Von Hippel-Lindau (VHL) and Cereblon (CRBN) are commonly used due to their well-characterized binding properties and suitability for drug design.
Therapeutic Applications
PROTAC technology offers a new way to remove disease-causing proteins across various diseases. In cancer, PROTACs target oncogenic proteins driving tumor growth. For instance, they can degrade androgen receptor (AR) in prostate cancer or estrogen receptor (ER) in breast cancer, which often resist traditional inhibitors. Degradation can be more effective than inhibition for targets where blocking activity is insufficient due to scaffolding functions or resistance.
PROTACs also show potential in neurodegenerative diseases like Alzheimer’s and Parkinson’s, characterized by misfolded protein accumulation. They could facilitate the clearance of these toxic aggregates, directly reducing harmful proteins contributing to neuronal damage.
Their applicability extends to infectious diseases, including viral infections, by degrading viral proteins or host proteins essential for replication. In inflammatory and autoimmune diseases, PROTACs could degrade key inflammatory mediators, dampening excessive immune responses.
Advantages and Current Challenges
PROTAC technology offers several advantages over traditional small molecule inhibitors. Their catalytic action means a single PROTAC molecule can degrade many target proteins. Unlike inhibitors, PROTACs are recycled after each degradation, potentially allowing for lower and less frequent dosing. This catalytic nature can also lead to more profound and sustained protein knockdown.
PROTACs can overcome drug resistance. By removing the entire protein, they address resistance from mutations or scaffolding functions not always tackled by inhibition. They can also target proteins lacking enzymatic activity or suitable binding pockets for conventional inhibitors. The requirement for two specific binding events (target and E3 ligase) can improve selectivity, potentially reducing off-target effects.
Despite these advantages, challenges remain for clinical adoption. Many PROTACs are larger than typical small molecule drugs, impacting their oral bioavailability, absorption, and distribution. Ensuring selective degradation without affecting other proteins is a concern, as off-target degradation could cause side effects. The number of E3 ligases with well-characterized ligands for PROTAC design is limited, restricting degradable targets. Toxicity, including immune responses, requires careful evaluation.
The Future of PROTAC Technology
The future of PROTAC technology involves continued innovation. A primary focus is expanding the repertoire of E3 ligases that can be recruited. Identifying new E3 ligase ligands will broaden the range of proteins targeted for degradation, potentially leading to more tissue-specific treatments. This expansion is important, given the large number of E3 ligases in the human genome.
Research also progresses on new targeted protein degradation modalities beyond traditional PROTACs. These include molecular glues, smaller molecules inducing proximity without a linker, and LYTACs (Lysosome-Targeting Chimeras) for degrading extracellular or membrane proteins. AUTACs (Autophagy-Targeting Chimeras) are another class focused on degrading organelles. These approaches aim to overcome PROTAC limitations and expand degradable targets.
Progress in clinical trials indicates the technology’s potential. Several PROTACs have advanced into human clinical trials, especially in oncology, with initial results generating interest. Continued success will validate protein degradation’s therapeutic utility. Developing PROTACs for combination therapies could enhance efficacy or overcome acquired resistance. The long-term vision includes tailoring PROTAC treatments based on a patient’s unique disease profile, moving towards personalized medicine.