The Chemistry Behind PROTAC®s, Molecular Glues, and ADCs: How to make the hardest modalities work

Advanced modalities like PROTACs, molecular glues, and Antibody Drug Conjugates (ADCs) are redefining the boundaries of drug discovery.

Their promise is clear but so is their complexity. These modalities demand a level of chemical and biophysical expertise far beyond that required for classical small molecules.

At Eurofins Discovery, we have spent years building the integrated capabilities and multidisciplinary teams needed to address these challenges with precision and confidence.

The PROTAC Challenge

The recent regulatory approval of Vepdegestrant marks a major milestone for targeted protein degradation, validating PROTACs as a therapeutic modality and accelerating industry investment. Designing a successful PROTAC, however, remains highly complex. It requires:

• Identification of ligands for both the protein of interest (POI) and the E3 ligase
• Rational linker design that preserves productive ternary complex formation
• Biophysical confirmation of ternary complex stability and cooperativity
• Optimization of permeability despite high molecular weight and polarity
• Early assessment of developability and scalability

Our chemists and biophysicists work within a tightly integrated workflow that combines parallel synthesis, advanced biophysical characterization, and AI-supported data analysis to accelerate design cycles and reduce risk.

The Molecular Glue Opportunity

Unlike PROTACs, molecular glues often arise from non-obvious or weak interactions, making them inherently more difficult to discover but potentially more elegant in their mechanism.

Our ultra-high-throughput spectral shift platform enables the identification of compounds capable of inducing or stabilizing POI–E3 interactions, even when traditional binary binding signals are minimal. This allows us to uncover opportunities that conventional screening approaches may miss.

The ADC Imperative: Precision Above All

Developing a successful ADC requires precise control over multiple interdependent parameters.

Key considerations include:

• Controlled drug-to-antibody ratio (DAR)
• High target selectivity and binding affinity
• Efficient cellular internalization (common, though not always required)
• Controlled payload release mechanisms
• Robust, scalable, and reproducible manufacturing processes

Our end-to-end workflow delivers this precision, from drug-linker conjugate (DLC) synthesis performed in dedicated high-potency labs, SEC purification, bioconjugation, LC-MS-based DAR determination, and functional assays including binding and internalization.

Learn more about our ADCs capabilities: https://www.eurofinsdiscovery.com/solution/antibody-drug-conjugate-development

A Case Where Everything Came Together

In a recent internal ADC project, we successfully generated a trastuzumab-based ADC demonstrating:

• Clear binding across three HER2 expression levels
• Verified internalization and cytotoxicity
• A scalable route ready for tox and CMC transition

Key Takeaways

• PROTAC workflows require validated ternary complex formation supported by biophysics
• Molecular glues can be identified using high-throughput spectral shift (HT-SpS) assays
• ADC development spans from DLC synthesis to confirmation of mechanism of action
• Drug-to-antibody ratio (DAR) is accurately quantified using LC-MS

Productivity Indicators

FAQ

Q: Why are ADCs so complex?

Because every component, antibody, linker, payload, and DAR, must function in harmony to achieve efficacy and safety.

Q: What’s special about Eurofins Discovery?

Deep chemistry expertise, high-containment infrastructure, and fully integrated workflows tailored to complex therapeutic modalities.