Validated High Throughput Screening Approaches For Molecular Glue Degrader Identification

Molecular glue degraders (MGDs) are a promising modality in targeted protein degradation (TPD), but their discovery remains a significant challenge, particularly beyond thalidomide-based compounds targeting CRBN. At Sygnature Discovery, we are developing novel approaches for the discovery of molecular glue degraders. This poster highlights the use of surface plasmon resonance (SPR) for the identification of molecular glues from compound libraries. We have demonstrated this approach by screening 10,000 lead-like compounds and 1,300 fragments for glue properties, using the Cereblon ubiquitin ligase and SOS1 and SHP2 proteins, as a model system.

Our Biophysical Screening Strategy

To identify novel MGDs modulating the KRAS pathway, we developed a highly sensitive SPR assay to detect ternary complex formation involving:

• The CRBN/DDB1 ubiquitin ligase complex
• The RAS-GEF domain of SOS1
• A diverse library of 10,000 lead-like compounds and 1,300 fragments

This work highlights SPR as a robust, scalable platform for medium-throughput molecular glue screening and early hit discovery

Integrated Expertise for Downstream Progression

Sygnature Discovery supports integrated TPD projects with a full suite of drug discovery capabilities:

• Orthogonal assay development (HTRF, imaging, proteomics)
• Medicinal and computational chemistry support for hit triage
• Deep domain knowledge across oncology-relevant targets

Download the full poster to explore how SPR and our screening expertise is unlocking new opportunities in molecular glue drug discovery – targeting SOS1, SHP2, and beyond.

At Sygnature Discovery, our expert screening teams are ready to support your journey from initial hit to validated degrader. Speak to us today to explore how our tailored platforms can accelerate your TPD programmes.