Since their initial publication in 2001, proteolysis-targeting chimeras (PROTACs) have rapidly progressed from an academic concept to a promising new therapeutic modality (1). Over the past two decades, they’ve captured the imagination of researchers for their potential to tackle disease-causing proteins that have long been considered “undruggable” using conventional small molecules.
Today, numerous companies are advancing PROTAC candidates from preclinical and early clinical stages to later phases of development, reflecting growing confidence in this emerging field (2). Yet translating PROTACs from the bench to the bedside involves more than innovative biology. It requires a robust, multidisciplinary framework, especially in pre-formulation and analytical development, to manage their unique complexities as drug molecules.
The Challenge of the ‘Undruggable’ Proteome
Despite decades of advances in small molecule and biologics-based therapies, the vast majority of disease-relevant proteins remain out of reach. An estimated 93% of the human proteome cannot be targeted using traditional drug discovery methods (3). This includes proteins such as transcription factors, scaffolding molecules, and mutant oncogenes that play critical roles in disease but lack the features necessary for conventional ligand binding.
To overcome these limitations, researchers are moving from traditional occupancy-driven pharmacology, where drugs must bind and inhibit their targets continuously, to event-driven pharmacology, where a temporary interaction is enough to trigger a lasting therapeutic effect. At the forefront of this evolution are targeted protein degraders and among them PROTACs stand out as a transformative modality.
PROTACs are designed not to inhibit, but to eliminate pathogenic proteins by hijacking the cell’s natural degradation machinery. This process occurs by recruiting the cell’s own ubiquitin-proteasome system to selectively degrade pathogenic proteins. As such, PROTACs offer the potential to address previously intractable targets, reduce off-target toxicity, and overcome resistance mechanisms.
Understanding PROTACs
PROTACs are heterobifunctional molecules consisting of two active domains: one that binds to a target protein of interest, and another that recruits an E3 ubiquitin ligase. These two ligands are connected by a linker. Once bound, the PROTAC facilitates proximity-induced ubiquitination of the target, leading to its degradation by the ubiquitin-proteasome system (UPS).
This event-driven mechanism represents a shift in how we approach drug design, with applications spanning oncology, neurodegenerative diseases, autoimmune disorders, and metabolic conditions. Focusing on the pipeline, oncology stands out as the most advanced therapeutic area. Notably, three candidates have reached Phase III trials (4):
- ARV-471 (Vepdegestran) targeting ER in ER+/HER2– breast cancer
- CC-94676 (BMS-986365) targeting AR in metastatic castration-resistant prostate cancer (mCRPC)
- BGB-16673 targeting BTK in relapsed/refractory B-cell malignancies (blood cancer)Despite the promise of PROTACs as a new therapeutic modality, significant challenges remain in translating these complex molecules into viable clinical candidates. Their development raises critical questions around manufacturability, formulation, and pharmacokinetics. Especially as many PROTACs, as well as many increasingly complex small molecules and other emerging modalities, fall outside the bounds of conventional drug design principles. For example, many PROTACs:
- Exceed molecular weights of 800 Da
- Violate multiple criteria in Lipinski’s rule of five
- Exhibit poor aqueous solubility, limiting oral bioavailability
- Are often difficult to crystallise, with associated issues of consistent isolation and impurity rejection
- Require tight control over dosing and impurity levels due to high potency
These properties strain conventional drug formulation techniques and complicate analytical method development. As more PROTACs enter late-stage development, addressing these issues will be critical to ensuring successful translation from bench to bedside.
Formulation and Physicochemical Challenges: Early decisions that shape success
As PROTACs transition from bench to clinic, one of the most critical and underestimated determinants of success lies in early-stage formulation decisions. Understanding the fundamental physicochemical properties of these molecules can significantly reduce downstream risks and accelerate development timelines.
PROTACs are structurally large, flexible, and often highly lipophilic molecules. These attributes contribute to their oftentimes poor aqueous solubility, low dissolution rates, and a strong tendency to exist in amorphous rather than crystalline forms. As a result, many PROTAC candidates suffer from low bioavailability and present challenges in purification, scalability, and long-term stability.
Key hurdles include:
- Crystallisation difficulty due to conformational flexibility and size
- Low intrinsic solubility and slow dissolution
- Propensity for aggregation or poor dispersion in formulation matrices
Failing to characterise and address these issues early can result in significant delays, increased costs, or even program termination. A well-executed pre-formulation strategy ensures that promising PROTAC candidates are not only potent in vitro but are also viable from a development and manufacturing standpoint.
Solid Form and Solubility Strategies: Turning challenges into opportunities
The poor solubility and often difficult-to-crystallise nature of PROTACs represent significant roadblocks to drug development. These complex molecules often challenge conventional formulation pathways.
Solid Form Optimisation: Building a reliable foundation
Due to their structural flexibility and large molecular weight, many PROTACs resist crystallisation, a common prerequisite for robust scale-up.
At Veranova, our approach is to address this through a tailored solid form programme that includes robust screening protocols of not only the parent PROTAC itself but where possible via salt and cocrystal modifications. The later may not only benefit crystallinity but can also fine tune a range of physical properties but notable solubility, dissolution and stability to name a few.
Here, solid form screening identifies developable solid forms and the most suitable for processing and scale-up. In the event that a crystalline PROTAC either as the parent, salt or cocrystal is not identified to aid isolation and development advanced purification techniques such as preparative chromatography are used to isolate and stabilise desirable forms. The result is a more predictable and process-friendly active pharmaceutical ingredient (API) that supports downstream formulation and regulatory progress, while also reducing the risk of late-stage surprises.
Particle Engineering: Tailoring particle performance
In parallel, particle engineering (PE) strategies can be applied to ensure that the physical properties of the API align with the needs of the final dosage form. Crystallisation development, a fundamental aspect of PE, has already been discussed in the context of PROTACs and their associated challenges. Given the solubility and dissolution limitations commonly observed with PROTACs, additional PE approaches are likely to be necessary. These may include a spectrum of particle size reduction techniques, ranging from conventional micronisation to advanced methods such as nano-milling. In summary, a range of techniques are at our disposal to control and modify particle size and morphology to facilitate the right particle for isolation,scale-up, and downstream formulation for patient dosing.
Amorphous Solid Dispersions (ASD): A reversed standard
Unlike traditional APIs, where amorphisation is a deliberate choice to enhance solubility, many PROTACs require ASD techniques as a primary route to functionality.
ASDs with PROTACs are in many ways analogous to complex small molecule APIs and can significantly increase dissolution rates and bioavailability, especially for oral delivery. There are well-trodden screening pathways coupled to scalable techniques (once an appropriate ASD is identified) such as spray drying and hot-melt extrusion. Our experience shows that when executed with precision, ASDs not only solve solubility challenges but also deliver physical stability and manufacturability at scale.
Empowering the Next Generation of Targeted Therapies
As PROTACs continue to open new frontiers in drug discovery, their path from promising concept to clinical reality remains complex. The challenges they pose, including poor solubility, crystallisation difficulties, and analytical complexity, result in knock-on effects during isolation and scale-up, and require specialised expertise and a proactive, collaborative approach to overcome.
By integrating pre-formulation science, advanced analytical methods, and tailored solid form and particle engineering strategies, CDMOs can help innovators unlock the full potential of these novel molecules. A CDMO with a proven track record in handling complex APIs, including PROTACs and other challenging modalities, will be able to ensure that each candidate is optimised not only for potency, but for manufacturability, stability, and clinical success.
PROTACs remove unwanted proteins by hijacking the cell’s natural degradation machinery, offering a radical new approach to treating a wide range of diseases.
Table 1. PROTACs in clinical trials for diseases with more than 30 PROTAC candidates currently in clinical trials targeting key proteins such as androgen receptor (AR), estrogen receptor (ER), Bruton’s tyrosine kinase (BTK), and interleukin-1 receptor-associated kinase 4 (IRAK4).(4)
Flowchart illustrating Veranova’s approach to development and scale-up of PROTACs – combining solid form optimisation, amorphous formulation, and targeted particle engineering to enhance bioavailability, stability, and manufacturability from the earliest development stages.
References and notes
- Sakamoto, K. M. et al. PROTACs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl Acad. Sci. USA 98, 8554–8559 (2001)
- Zhong, G. et al. Targeted protein degradation: advances in drug discovery and clinical practice. Sig Transduct Target Ther 9, 308 (2024).
Kana, O., & Brylinski, M. (2019). Elucidating the druggability of the human proteome with e findsite. Journal of computer-aided molecular design, 33, 509-519.
https://clinicaltrials.gov
