Unlike conventional small-molecule inhibitors that merely suppress protein activity, TPDs leverage the body’s degradation machinery to permanently remove harmful proteins.
This innovative mechanism opens the door to new treatments in oncology, neurodegenerative disorders and immune-related conditions, reports Rebecca Coutts, Senior Director, Pharmaceutical Development at PCI Pharma Services.
Investment in the field has followed suit; venture financing for TPDs jumped from $33 million in 2017 to $707 million in 2022, representing a rise of more than 2000%.1
The global market, valued at approximately $544.4 million in 2024, is forecast to grow at a CAGR of 20.8% from 2025 to 2030.2
Yet, despite their promise, TPDs face significant hurdles, including challenges in terms of formulation, bioavailability and manufacturing scalability.
The growing promise of targeted protein degraders
The scientific rationale behind TPDs lies in their ability to selectively and irreversibly eliminate specific proteins by leveraging the body’s ubiquitin-proteasome system.
Whereas traditional therapies such as tyrosine kinase inhibitors (TKIs) aim to block protein function, they often result in temporary suppression and can lead to drug resistance with time.
TPDs go a step further by binding to the target protein and directing it toward degradation, thereby offering a more durable response. This approach is particularly advantageous when conventional small-molecule inhibitors struggle to achieve sufficient specificity or efficacy.
TPDs are showing considerable promise in oncology, with applications in lung and breast cancer, multiple myeloma and lymphoma.
Their potential extends beyond oncology, with researchers actively exploring their use in neurodegenerative conditions such as Parkinson’s disease where protein misfolding and aggregation contribute to its progression.
Immunological conditions are another key area of interest as TPDs offer new opportunities to selectively remove proteins that drive chronic inflammation and immune dysregulation.
Given that the human body contains thousands of proteins with varied functions, the potential applications of TPDs are vast, making them one of the most exciting frontiers in drug development.
Among the most widely explored TPD strategies are proteolysis-targeting chimeras (PROTACs) and molecular glues, both of which are already in clinical trials.
PROTACs are bifunctional molecules that simultaneously bind to the target protein and an E3 ubiquitin ligase to initiate the degradation process.
Molecular glues, by contrast, work by enhancing the interaction between a target protein and a ubiquitin ligase, effectively recruiting the body’s degradation machinery more subtly and efficiently.
As these technologies continue to advance, they are poised to reshape the therapeutic landscape.
Development challenges of TPDs
The therapeutic potential of TPDs is undeniable, but their development is fraught with complexities.
Unlike traditional small-molecule drugs, which typically conform to well-established pharmacokinetic and pharmacodynamic principles, TPDs often exhibit atypical properties that make formulation and delivery more challenging.
One of the primary formulation challenges stems from the molecular structure of TPDs. Their higher molecular weights, combined with the presence of the functional groups needed for target binding and E3 ligase recruitment, often result in poor solubility and limited permeability.
These characteristics can hinder oral bioavailability, necessitating the use of advanced formulation strategies to improve drug absorption. Molecular glues, which tend to be smaller, have shown greater promise for oral delivery whereas PROTACs often require additional solubility enhancement techniques.
The challenge of poor solubility has prompted researchers to explore a range of formulation approaches, including hot-melt extrusion, spray drying, nanomilling and lipid-based formulations.
Each technique presents unique advantages depending on the physicochemical properties of the TPD in question.
For example, spray drying and hot-melt extrusion can enhance the bioavailability of poorly soluble compounds by producing amorphous solid dispersions, whereas nanomilling reduces particle size to increase dissolution rates.
Lipid-based formulations, meanwhile, can leverage the body’s natural lipid absorption pathways to improve drug uptake. The complexity of TPDs also extends to their compliance with Lipinski’s Rule of Five, a widely used guideline to predict oral drug absorption.
Many TPDs fall outside these parameters, exhibiting characteristics such as high molecular weight, poor permeability and increased hydrogen bond donor/acceptor counts.
Overcoming these hurdles requires extensive solubility screening and optimisation at an early stage to ensure that the selected formulation strategy aligns with the intended route of administration.
Additionally, excipients play a crucial role when it comes to stabilising formulations and ensuring uniform dosage, particularly given the low drug loads typical of highly potent compounds such as TPDs.
Manufacturing and stability considerations
Manufacturing TPDs requires a sophisticated approach that balances potency, bioavailability, scalability and stability. Given their targeted mechanism of action, these compounds are often highly potent and require stringent containment measures to ensure safe handling during production.
The need for high-containment manufacturing environments means that not all facilities are equipped to handle TPDs, making CDMO partnerships an essential component of successful development.
Beyond containment, the stability of TPDs presents another significant challenge. The intricate molecular structures that enable their targeted degradation capabilities can also make them more susceptible to degradation under certain conditions.
Ensuring formulation stability throughout scale-up and commercial production requires the careful selection of excipients, processing techniques and analytical monitoring methods.
Robust in-process controls are essential to maintain consistency and ensure that the final drug product meets regulatory standards.
The role of CDMOs in TPD development With the increasing complexity of drug development, biotech and pharmaceutical companies are turning to specialised CDMOs to navigate the challenges associated with TPDs.
CDMOs such as PCI Pharma Services bring deep expertise in potent compound handling, advanced formulation techniques and high‑containment manufacturing, providing the critical infrastructure needed to support the transition from preclinical development to commercial supply.
Analytical development is another area wherein CDMOs play a vital role. Characterising TPDs requires highly specialised techniques such as surface plasmon resonance, mass spectrometry, fluorescence polarisation, X-ray crystallography and bio-NMR spectroscopy.
These methods provide crucial insights into the stability, binding efficiency and degradation kinetics of TPD candidates. Because these techniques demand significant expertise and infrastructure, many companies rely on CDMO partnerships to access the necessary analytical capabilities.
PCI Pharma Services, leveraging more than 35 years of experience in high-potency drug development, has also established strategic partnerships to expand its capabilities in solubility enhancement and particle engineering.
Through well-established enabling technologies such as hot-melt extrusion, spray drying and nanomilling, PCI can enable the successful formulation of TPDs that might otherwise struggle with poor bioavailability and inconsistent performance.
The future of targeted protein degraders
Driven by advancements in medicinal chemistry, structural biology and computational modelling, the landscape of TPD research is evolving rapidly.
The next 5–10 years are expected to see a surge in new TPD candidates, with particular emphasis on improving oral bioavailability and expanding the range of targetable proteins.
Advances in E3 ligase ligand discovery and optimisation will further refine TPD design, making them more selective and efficient in their degradation mechanisms.
The integration of artificial intelligence (AI) and machine learning (ML) into drug discovery is poised to accelerate the identification of viable TPD candidates, subsequently reducing development timelines and increasing success rates.
AI-driven high-throughput screening will enhance molecule selection, allowing researchers to identify the most promising compounds before moving to the labour-intensive stages of synthesis and testing.
As regulatory frameworks for TPDs continue to take shape, engaging with agencies early in development will be crucial to ensure compliance and streamline the approval process.
CDMOs will remain instrumental in terms of guiding companies through these evolving requirements by leveraging their expertise to optimise formulations, select appropriate enabling technologies, scale-up production and deliver stable, high-quality drug products.
Conclusion
Offering a highly selective and irreversible approach to protein elimination, targeted protein degraders represent a paradigm shift in drug development.
Although their optimisation presents unique challenges, the expertise of CDMOs is helping to overcome these barriers and enable the successful transition from research to clinical application.
As scientific and technological advancements continue to accelerate, the future of TPDs looks exceptionally promising; they’re paving the way for groundbreaking treatments that could redefine the landscape of modern medicine.
References
- Venture financing for targeted protein degraders soared in 2022.
- Targeted Protein Degradation Market Size, Share & Trends Analysis Report.
