Plexium utilizes the DELPhe platform to identify E3 ligase modulating small molecules

DELPhe =  DNA-Encoded Library (DEL) + Phenotypic screening (Phe)  

The DELPhe platform combines the scale achievable with DNA-encoded library screening with deep multiplex phenotypic analysis only available by cell-based screening

The DELPhe platform combines “on-bead” DNA encoded libraries with ultra-high-throughput miniaturized cell-based assays to enable screening of highly diverse chemical space. Plexium is utilizing the DELPhe platform to identify monovalent direct degraders or molecular glue degraders targeting pathogenic proteins.

Experiments are performed in picowells with a single bead coated with millions of copies of a given small molecule and millions of copies of the associated DNA tag. Small molecules can be released from the bead in a controlled dose via a photocleavable linker. Cell lysates are analyzed across selected biological readouts, providing rich information on small molecule activity.


Advantages of DELPhe
  • DELPhe, next-generation DEL combinatorial library approach designed to identify cell-active degrader drug candidates
  • DNA tag is attached to the bead, not to the small molecule, so it does not interfere with the assay or create target binding artifacts
  • Extends DNA-encoded library screening to cell-based assays eliminate spacing between hyphens
  • Primary assay readout is the identification of compounds that degrade a target of interest in representative cells

Targeted protein degradation with molecular glues and direct degraders

Plexium uses the DELPhe platform to identify
novel E3 ligase molecular glues and direct
degraders of disease-relevant proteins

The DELPhe platform enables us to discover new E3 ligase molecular glues and direct degraders of proteins which are important in cancer and other serious diseases


Protein degradation offers advantages over traditional inhibitor drugs with the potential to deliver improved efficacy and safety, and through targeting proteins without a defined small-molecule binding site

Targeted protein degradation enables the selective modulation of protein levels within the cell, including complete degradation of a specific target protein which results in total loss of protein function. Plexium employs the DELPhe platform to obtain a broad view on the cellular response to protein depletion via E3 ligase modulation. Profiling E3 ligase modulating small molecule libraries or compound libraries which direct a protein of interest to an E3 ligase enables the development structure-activity-relationships and is expected to reduce hit-to-lead and lead optimization cycle times. The primary assay readout is degradation of the protein of interest, treating cells with hit compounds and proteasome inhibitors enables rapid confirmation of a proteasome-dependent mechanism of action.

Unique advantages of E3 ligase manipulation for first-in-class therapeutics:

  • Enables re-direction of naturally occurring protein quality control machinery to degrade pathogenic proteins
  • Expands the druggable proteome to proteins without well-defined binding pockets
  • Opportunity for improved efficacy over “inhibitors” due to loss of target protein function until completion of protein resynthesis 
  • Monovalent degraders are expected to have improved drug-like properties compared to heterobifunctional protein degraders