Designing Proprietary, Bespoke Target-Centric and E3 Ligase Libraries

We use proprietary degrader-centric medicinal chemistry approaches to design chemical libraries with maximum potential to induce protein-protein interactions resulting in highly selective target degradation.

• Target and modality-centric chemistry approach, leveraging bespoke library design and synthesis for each drug discovery program
• AI-guided structure-based drug design accelerates the discovery of monovalent degraders
• Solid phase and combinatorial chemistry approaches for dense interrogation of structure-activity relationships
• One of the largest (1+ million) on-bead Cereblon binder libraries available for molecular glue screening
• Compound designs focused on optimizing drug-like properties

Leveraging Functional Readouts in Disease-Relevant Cell Types at Ultra High-Throughput

We utilize disease relevant, cell-based protein depletion assays as primary screens. This enables the rapid identification of drug-like, cell-permeable monovalent degrader molecules in the appropriate cellular context.

• Disease relevant assays include representative cells lines (adherent/non-adherent) or those derived from induced pluripotent stem cells (iPSCs)
• Miniaturized Picowell devices screen millions of compounds in days
• Chem- and bio-informatics support a deep understanding of how small molecule binders can be optimized to induce target selective degradation
• Device breadth enables understanding of structure-activity relationships (SAR) that convert small molecule binders into degraders
• Direct degraders are identified by screening bespoke libraries enriched for binders toward a protein of interest and allow discovery of novel E3 ligases harnessing the intrinsic cellular machinery

Generating Comprehensive, Actionable Datasets for Difficult-to-Drug Targets

We leverage post-hit confirmation workflows to characterize ternary complex formation (target protein-Plexium Degrader-E3 ligase), including E3 ligase identification and degradation machinery to reveal mechanism of action. Degrader-centric CRISPR knockout screens are used to discover novel E3s.

• Cutting edge “omics” approaches for characterization of cellular response to target depletion and assessment of degrader selectivity
• High-throughput global proteome profiling to understand selectivity against off-target proteins
• Protein-protein interaction network mapping and chemoproteomics analysis of protein-drug interactions
• Bulk and Picowell RNASeq transcriptomics being developed to map high content imaging with biological activity for a given cellular background
• Levering AI-driven image analysis to train models and rapidly iterate screening to library expansion