In the relentless pursuit of modern medicine, Targeted Protein Degradation (TPD) has emerged as a revolutionary therapeutic strategy, offering new hope for the treatment of numerous diseases. Traditional small-molecule inhibitors mainly act by inhibiting protein function, while TPD technology adopts an innovative approach by leveraging the intracellular proteolysis systems, such as the proteasome and lysosomedegara pathways, to specifically degrade pathogenic proteins. This novel technique provides a fresh perspective and methodology for disease treatment. It not only enhances therapeutic efficacy but also broadens the spectrum of treatable diseases, offering hope for targets previously considered “undruggable.”
1. Development and Breakthroughs in TPD Technology
1.1 Evolution of TPD Technology
The development of TPD technology has progressed from the introduction of its concept to a clearer understanding of its mechanisms.
- In 1999, Proteinix introduced the concept of targeted protein degradation through a patent application, initiating exploration into TPD technologies.
- During the early “foggy era,” the mechanisms of action of protein degraders remained unclear, and research progressed relatively slowly.
- Over time, in the “interpretation era,” scientists began to elucidate related molecular mechanisms, such as the development of proteolysis-targeting chimeras and a deeper understanding of molecular glue (MG) mechanisms.
- In recent years, TPD technology has entered its “golden era,” with numerous novel MGs and Targeted Protein Degradation emerging and advancing to clinical trial stages. For instance, TPD drugs have shown remarkable therapeutic potential in areas like hematologic malignancies, solid tumors, and neurodegenerative diseases.
1.2 Diverse Strategies of TPD Technology
Current TPD technologies primarily utilize three protein degradation pathways, each with unique applications and advantages:
- UPS-Based TPD Technology: Typically enhances protein of interest (POI) ubiquitination through specific E3 ubiquitin ligases followed by proteasome degradation, suitable for intracellular soluble proteins. Targeted Protein Degradation, a major UPS-based TPD technology, promote POI ubiquitination and degradation via ternary complexes. These agents are recyclable but face challenges like the hook effect, and optimization is ongoing. MGs, another approach, regulate protein-protein interactions (PPIs) for degradation. Although MGs are small, permeable, and discovered incidentally, their design is complex, with only a few approved for clinical use.
- EL Pathway-Based Degraders: Examples include LYTACs and MoDE-As, which typically induce interactions between POIs and membrane receptors, resulting in endocytosis and subsequent lysosomal degradation. These are limited to extracellular or membrane proteins.
- Autophagy-Based Technologies: Methods like ATTECs or AUTOTACs degrade targets by enhancing the recognition of POIs by autophagosomes. Autophagy occurs mainly in the cytoplasm and can degrade soluble proteins, nucleic acids, lipids, protein aggregates, organelles, and even pathogens.
Some TPD technologies involve multiple degradation pathways. For example, proteolysis-targeting antibodies (PROTABs) hijack the transmembrane E3 ligase ZNFR3 and may trigger targeted degradation through both the UPS and EL pathways.
Among TPD technologies, each method demonstrates unique characteristics and potential. UPS-based Targeted Protein Degradation technology currently leads clinical research and is developing rapidly.
Looking ahead, the trend toward diversification in TPD technologies is increasingly evident. Especially with the deeper exploration of autophagy and EL pathways may open new avenues to address numerous “undruggable” targets, greatly expanding the boundaries of disease treatment.
2. Clinically Advanced Protein Degraders
Significant progress has been made in clinical research on protein degraders. According to incomplete statistics:
- Globally, 36 protein degraders have entered clinical stages.
- Over 1,000 TPD-related R&D pipeline projects are underway worldwide.
- In China, nearly 80 companies or institutions are actively involved, driving over 380 R&D pipelines, with 35 already in clinical development stages.
Although all approved drugs and 90% of clinical drugs are concentrated in oncology, protein degraders have also made advances in other therapeutic areas, such as neurology and immunology. Currently, preclinical studies in neurology (11%) and immunology (6%). Heterobifunctional degraders (e.g., ARV-102, KT-474) and molecular glues (e.g., BMS-986419, MRT-6160) are undergoing clinical trials.
Moreover, an increasing number of protein degrader pipelines are targeting traditionally undruggable targets (e.g., IKZF1/3, GSPT1, VAV1, WIZ, BCL6) are becoming increasingly accessible. This transformation reflects the widening scope of TPD applications, presenting both new opportunities and challenges for drug development.
3. Four Key Innovations in Targeted Protein Degradation
As an emerging therapeutic strategy, TPD technology’s preliminary clinical results have been promising. It offers new hope for the treatment of many diseases due to its unique mechanism of action. During early research and exploration, TPD demonstrated potential for addressing specific disease-related proteins, sparking optimism for overcoming some intractable diseases.
However, it is important to recognize that TPD technology faces challenges, including issues of safety, efficacy, and disease indication range. The next generation of degrader technologies aims to overcome these limitations through innovations in ligands, pathways, delivery mechanisms, and activation methods.
3.1 Ligand Innovations
New ligands for E3 ligases and target proteins (POIs) offer pathways to expand new targets and improve tissue specificity, thereby enhancing disease applicability and safety. Although there are over 600 human E3 ligases, almost all current degraders recruit ubiquitously expressed Cereblon.
Alternative E3 ligase recruitment domains, such as tumor-overexpressed HSP90 chaperone complexes in chaperone-mediated protein degraders (CHAMP) or tissue/tumor-specific E3 ligases, can restrict TPD activity to cancer cells, reducing off-target effects.
Additionally, alternative POI ligand components can broaden the scope to more “undruggable” targets. For instance, RNA-degradation use short oligonucleotides to degrade ribonucleoproteins. Preliminary results for a novel E3 ligase ligand degrader (CHAMP-RNK05047) are expected by the end of 2024.
3.2 Pathway Innovations
Alternative pathways to the ubiquitin-proteasome system can expand the range of addressable targets and overcome E3 ligase resistance. Examples include:
- Extracellular proteins: Molecular degraders like MoDEs and lysosomal-targeting chimeras (LYTACs) utilize the endosome-lysosome pathway to target extracellular proteins.
- Autophagy-Targeting Chimeras (AUTACs): Use the autophagy-lysosome pathway, providing E3 ligase-independent mechanisms for degrading intracellular proteins and organelles.
While preclinical results have been promising, early clinical results have been mixed. For example, MoDE BHV-1300 achieved 60–80% degradation in preclinical studies but only 37% at maximum dose in mid-phase I trials.
3.3 Delivery Innovations
TPDs can leverage advances in degrader-antibody conjugates (DACs), nanotechnology (Nano-Targeted Protein Degradation), and click chemistry (CLIPTACs) to improve specificity and efficacy.
- DACs identify receptors expressed on target cells.
- Nano-Targeted Protein Degradation respond to tumor-specific conditions, enabling concentrated delivery to cancer cells.
- CLIPTACs use two smaller self-assembling parts for oral bioavailability, although they must assemble intracellularly to remain cell-permeable.
DACs stand out particularly, with nine currently in clinical research stages. BMS-986497 and ORM-5029 are in phase I trials.
3.4 Activation Innovations
Targeted activation can control spatial and temporal degradation, whether in response to light (PHOTACs), hypoxia (hypoxia-activated Targeted Protein Degradation), or additional POIs (trivalent Targeted Protein Degradation).
However, practical limitations exist:
- Limited tissue penetration of light constrains PHOTAC activation.
- Naturally hypoxic tissues limit hypoxia-activated Targeted Protein Degradationspecificity for tumors.
- Additional bulk may limit oral bioavailability for trivalent Targeted Protein Degradation.
Below is a table listing the services and products provided by Creative Biolabs on our Protein Degraders solution. Each entry includes a brief description and a link to the detailed offering.
| Service | Product |
| Molecule Discovery | Linkers |
| In Vitro Evaluation | Ligands |
| In Vivo Animal Tests | E3 Ligase Proteins |
| Innovation and Customization | Target Proteins |
| Protein Degrader Platform | Protein Degraders |
This table provides a quick overview of the key services and innovative products offered by Creative Biolabs in the field of protein degraders.