Discovering Next Generation Targeted Protein Degrader Drug Candidates

Publications & Presentations

Plexium has a highly differentiated drug discovery approach, which has led to the discovery of novel, selective, targeted protein degraders with the potential to address diseases with significant unmet medical needs. We integrate degrader chemistry design principles to build libraries and screen in cell-based, target-specific degradation assays. Our ultra-high throughput screening platform accelerates the identification of drug-like, cell-permeable monovalent degrader drug candidates.

Publications & Presentations

Monovalent Direct Degraders

  • Small drug-like molecules that bind to the protein of interest (POl)
  • Rapidly design Direct Degraders using existing chemical starting points
  • Plexium’s cell-based screening platform has identified multiple novel E3 ligases and expanded the TPD toolbox
  • Chemistry design principles transferable across targets

Molecular Glue Degraders

  • Small drug-like molecules that bind E3 ligases to induce POI degradation
  • Plexium has implemented a Molecular Glue strategy to target “undruggable” proteins
  • Large on-bead library for screening and accelerating hit identification
  • “Focused diversity” around key E3 binding elements
Plexium Med Degrader Glue Pathway

Plexium’s Proprietary Approach

Plexium Library
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Prospective Design

Next Level Monovalent Degrader Design Insights

We use proprietary degrader-centric medicinal chemistry insights to design molecules with the potential to induce protein-protein interactions that result in selective target degradation.

  • Target-centric chemistry approach, bespoke compound and library synthesis for each drug discovery program
  • Structure-based drug design accelerates the discovery of monovalent degraders
  • Solid phase and combinatorial chemistry approaches for dense interrogation of structure-activity relationships
  • Compound designs focused on optimizing drug-like properties
  • Proprietary cell-based uHTS system allows screening of millions of compounds
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Cell-Based Screening

Discovering Degrader Drug Candidates in a Disease Relevant Background

Our approach is based upon utilization of disease relevant, cell-based assays as primary screens. This approach enables the identification of drug-like, cell-permeable monovalent degrader molecules in the appropriate cellular context. Chem- and bio-informatics support a deep understanding of how small molecule binders can be optimized to induce target selective degradation.

  • Disease relevant assays are comprised of representative tumor cells lines or derived from induced pluripotent stem cells (iPSCs)
  • Primary assay endpoint is depletion of a pathogenic protein induced by a cell active small molecule degrader
  • Enables understanding of structure-activity relationships (SAR) that convert small molecule binders into degraders
  • Direct degrader compounds are identified by screening E3 ligase agnostic libraries; this allows us to harness novel E3 ligases that are selected by the cellular machinery
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Ultra-High Throughput Screening

A Proprietary, Ultra-High Throughput Cell-Based Screening Platform

Our integrated, targeted protein degradation drug discovery platform supports screening of large compound libraries with a variety of readouts: protein degradation, phenotypic or transcriptomic response.

  • Microfluidic devices with up to 88,000 picowells
  • One compound per well assays are enabled by on bead, DNA encoded combinatorial compound libraries with photorelease
  • Machine learning algorithms and next-gen sequencing support identification of hit compounds
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Genomic Analysis

Suite of Technologies Provides Deep Insight into the Biology of Targeted Protein Degradation

Diversified approach to characterization of ternary complex formation (target protein-Plexium Degrader-E3 ligase), including identifying E3 ligase and degradation machinery. Cutting edge “omics” approaches for characterization of cellular response to target depletion and assessment of degrader selectivity.

  • Degrader-centric CRISPR knockout screens
  • High-throughput global proteome profiling
  • Protein-protein interaction network mapping
  • Chemoproteomics analysis of protein-drug interactions
  • Bulk and Picowell RNASeq transcriptomics