Building a platform of validated high throughput screening approaches for molecular glue degrader identification

Over recent years, Induced proximity therapeutics (IPT) and targeted protein degradation (TPD) approaches have become increasingly popular.  Whilst significant initial efforts focussed upon heterobifunctional degraders, molecular glue degraders (MGDs) represent the next generation of proximity-based drugs, but their rational discovery remains challenging.

The majority of reported glues are derived from known IMiD derivatives, such as pomalidomide and lenolidomide. There are currently few described approaches for unbiased hit identification of novel molecular glues. Here, we describe three scalable methods based on SPR, HTRF and High Content Imaging, forming a comprehensive discovery platform for molecular glues. Although this work is focused on degraders, the described approaches are compatible with effector proteins beyond ubiquitin ligases, such as deubiquitinases.

In our AACR poster, we showcase our unbiased and broadly applicable approaches for molecular glue hit ID through the development of a suite of orthogonal and highly complementary screening approaches, relying on Homogeneous Time-Resolved Fluorescence (HTRF), Surface Plasmon Resonance (SPR) and High Content Imaging (HCI). Together, these approaches demonstrate multiple, complementary options for identifying molecular glue degraders and for characterising bifunctional degrader compounds.

This platform is poised to identify high-quality hit compounds across a range of oncology targets of high unmet clinical need. Once promising starting points are identified, these can be further optimised toward meaningful therapeutics, utilising our extensive expertise in biophysical characterisation of ternary complex formation (including SPR, MST, Fida), structural biology (including CryoEM), cellular degradation assays (e.g. Protein Simple Jess assays) and our in vivo DMPK capabilities.

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