DELs in Cells – Molecular Glue Direct – Tap into the potential of molecular glue

Unlocking the potential of targeted protein degradation (TPD) through the cellular ubiquitin-proteasome machinery represents a paradigm shift in drug discovery, broadening the scope of druggable targets. This process involves stabilizing a complex between the protein of interest (POI) and one of the 600+ E3 ubiquitin ligases encoded by the human genome, promoting POI ubiquitination and subsequent degradation.

The TPD field has been spearheaded by heterobifunctionals, such as PROTACS, whereas only a limited set of molecular glues have been discovered and advanced. Heterobifunctionals are easier to discover but more difficult to advance due to their size/physiochemical properties and the “hook effect”. In contrast molecular glues are more difficult to discover but easier to advance due to their better physicochemical properties and mode of action.

Our unique DEL – Molecular Glue Direct service takes advantage of our unique capability for multiplexing. POI(s) and E3 ubiquitin ligase(s) are screened in a multiplexed format and compared to the monoplexed screens. 

• Simple fee-based plan with no reach-through and royalty payments
• Hit exclusivity and transparent cost structure – Client owns all hits and foreground IP without any downstream financial obligations
• The compensation plan comprises a total of 3 payments as a transparent cost structure
  • Pre-Project Expression Study Fee – scales with work
  • Screening Fee – scales with screening slots
  • Chemical Series Nomination Fee
• The project flow is rapid and straightforward: 
  • Client provides the amino acid sequence for the target protein
  • Vipergen performs the Expression Study (go-no-go)
  • Vipergen performs one round of screenings with varying constructs and different libraries. 
  • Vipergen delivers a hit list and report, including metrics from screens and chemical structure information 
  • Hits are reserved for client for 1 year
  • Client may resynthesize and test hits in relevant assays and use data for 1 year 
    • Vipergen can assist in off-DNA resynthesis as a fee-for-service
  • Client may nominate Chemical Series for 1 year 
  • Vipergen assigns its rights to Nominated Chemical Series, and these become exclusive for you as a client
    • Client own all foreground IP, data and hits of nominated series without royalty payment or other downstream financial obligations

DELs in Cells – Molecular Glue Direct enables the discovery of molecular glue molecules by screening the POI(s) in a living cell, using our cellular Binder Trap Enrichment (cBTE) technology in our unique multiplexed format.

The multiplexing capability allows for the simultaneous screening of multiple proteins, including a POI and an E3 ligase, in the same living cell. This is achieved by tagging each target protein with barcoding DNA, and using the barcode to enable the discovery of compounds binding to the POI, the E3 ligase, and the complex between them, respectively. 

In the subsequent analysis, molecular glues are identified as the molecules that are found as shared hits between the POI and the E3 ligase.

The multiplexing cBTE technology can also be used for identifying molecular glues in more general cases, where the interaction partners do not include an E3 ligase, and can even be used to identify inhibitors of protein-protein interaction directly.

DELs in Cells – Molecular Glue Direct screen. DEL and target binding DNA (Bait-DNA) are co-injected, binding allowed to take place, and the DNA ligated in emulsion. Molecular glue hits are observed as shared hits between the POI and the E3 ligase.

Vipergen’s high fidelity DELs are synthesized using robust chemistry and with a purification steps after each chemical transformation, thus providing 100% correspondence between code and compound (no truncates).

Key drivers for library design

• Chemical diversity
• Physicochemical properties
• Fidelity
• Hit resynthesis (off DNA)

DEL screening 

DEL design and synthesis