Unlocking the Future of Targeted Protein Degradation With Axcelead’s DegLead™ Platform
Scientist
on
May 30, 2025
This blog post was written by Axcelead Drug Discovery Partners, your trusted drug discovery and development partner. Their services are available on the Scientist.com marketplace.
Targeted Protein Degradation (TPD) has emerged as one of the most promising modalities in drug discovery, offering new therapeutic opportunities for previously “undruggable” targets. However, the development of clinical degraders — whether bifunctional degraders such as PROTACs or molecular glue degraders (MGDs) — remains challenging.
At Axcelead Drug Discovery Partners, our proprietary DegLead™ platform provides fully integrated drug discovery services designed to accelerate and de-risk TPD drug discovery across all stages of non-clinical development.
DegLead™ Platform for TPD Drug Discovery
Not just a service - It’s a full-spectrum solution that:
- Supports all stages of non-clinical development for your TPD programs
- Enables the efficient and high-probability generation of orally available bifunctional degraders (e.g., PROTACs)
- Facilitates the discovery of molecular glue degraders (MGDs) through robust and validated methodologies.
Discover how DegLead™ overcomes the unique challenges of bifunctional and molecular glue degraders.
1. Bifunctional Degraders – Complex Optimization and Poor in vitro-in vivo correlation（IVIVC)
Developing highly potent, orally bioavailable bifunctional degraders is a significant challenge. Drug developers frequently face:
- Time-intensive optimization due to the vast number of possible structural modifications and combinations (PoI binders, linkers, E3 ligase binders)
- Poor IVIVC, which complicates rational design for oral bioavailability.
DegLead™ Solution: Proprietary High-Throughput Chemistry Platform
Bifunctional degraders require the exploration of an extensive range of structural combinations, making high-throughput synthesis essential. Traditional approaches using degrader chemical toolboxes - where E3 ligase binders are pre-linked to linkers - offer limited chemical diversity and are typically effective only for initial hit generation.
Axcelead’s proprietary multi-step high-throughput synthesis platform enables the flexible assembly of PoI binders, linkers and E3 ligase binders. With access to thousands of ready-to-use linkers, we can rapidly explore broad chemical space, accelerating the identification of lead compounds and preclinical candidates.
For E3 ligase binders, our degrader chemical toolbox includes over 40 CRBN binders - the most validated class for orally bioavailable degraders - further streamlining the generation of drug candidates. Additionally, our platform supports the integration of client-supplied E3 ligase binders, allowing for tailored solutions based on each partner’s proprietary assets.
Moreover, we have accumulated PoI binders for over 500 drug targets, including many non-public compounds. Some of these binders possess desirable properties for bifunctional degraders, such as low molecular weight and high selectivity, offering unique value in specific discovery programs.
DegLead™ Solution: Proprietary High-Throughput ADME Screening
Even for orally available bifunctional degraders, conventional in vitro assays often fail to accurately assess membrane permeability. Similarly, standard solubility assays frequently show poor correlation with in vivo pharmacokinetic (PK) profiles. As a result, researchers typically rely on physicochemical properties to estimate oral bioavailability - an approach that provides only generalized trends and is prone to outliers.
At Axcelead, we have addressed these limitations by developing a proprietary, high-sensitivity membrane permeability assay system. In parallel, we have built extensive expertise and datasets in solubility assessment, enabling us to design a highly effective screening workflow tailored specifically to the challenges of orally available bifunctional degraders.
Our platform supports all essential ADME evaluations required for degrader development - including parameters such as EPSA - and delivers results within one week of assay request. By leveraging Axcelead’s ADME solutions, the probability of successfully generating an orally administrable bifunctional degrader is significantly enhanced.
Acheivements
In a recent case study, Axcelead successfully enabled:
- Discovery of an orally available degrader with a DC₅₀ in the nanomolar range and favorable ADME profiles - achieved within just 4 months.
- Over 90% of newly synthesized compounds demonstrated oral absorption, with several showing oral bioavailability (BA) exceeding 20%.
2. Molecular Glue Degraders (MGDs) – Validated Hit Identification
The discovery of molecular glue degraders requires a high-quality starting point and robust validation technologies. Key challenges include:
- Difficulty in identifying active compounds in the absence of established structure – activity relationships (SAR).
- Need for advanced screening, hit validation and profiling technologies to confirm degrader activity and mechanism.
DegLead™ Solution: High-Quality Compound Libraries, Including MGD-Focused Sets
Axcelead offers:
- A 1.2+ million-compound library inherited from major pharmaceutical companies.
- A focused library of 6,400 compounds, including over 600 binders of several E3 ligases, specifically designed for molecular glue degrader screening.
DegLead™ Solution: Advanced Assay Platforms and Profiling Technologies
Axcelead supports discovery and validation through:
- Robust assay systems: HiBiT, NanoBRET, TR-FRET, AlphaLISA, AS-MS, SPR and more.
- Omics-based profiling: including global proteomics and proximity labeling.
- Mechanistic validation: confirming E3 ligase dependency and degradation pathways.
Together, these assets and capabilities enable the confident identification of true molecular glue degraders - not just preliminary hits.
While having the right technologies is essential for MGD discovery, it is deep scientific expertise and advanced know-how that truly drive success. At Axcelead, we not only possess the necessary tools, but also the insight to apply them effectively.
Our team’s comprehensive understanding of degradation mechanisms, E3 ligase biology and the complexities of molecular glue development allows us to overcome the inherent challenges of this modality. With DegLead™, our partners can move beyond hit identification and fully unlock the therapeutic potential of molecular glue degraders.
Partner with Axcelead to Revolutinize TPD Discovery
Axcelead integrates all essential preclinical drug discovery functions - chemistry, screening, pharmacology, DMPK, safety - under one roof. With advanced instrumentation, expert researchers and a wealth of drug data, we provide integrated or tailored solutions for your TPD program from target identification to preclinical candidate. Let us help you unlock the full potential of Targeted Protein Degradation.
