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.
Experiments are performed in picowells with a single bead coated with a given small molecule and associated DNA tag in each well. Small molecules can be released from the bead in a controlled dose. Cell lysates are analyzed in a multiplex manner across selected biological readouts, providing rich information on small molecule activity.
Advantages of DELPhe
- Rapid synthesis and screening of DNA-encoded libraries at low cost
- DNA tag is on bead, not small molecule, so does not interfere with assay or create artifacts
- Extends DNA-encoded library screening to functional and cell-based assays
- Dose-response screening for cell-permeable small molecules possible in primary screen
- Picowell format enables assays where reagent quantities are limiting
Redirecting E3 Ligases
Plexium utilizes DELPhe to identify E3 ligase binding small molecules with novel profiles
The DELPhe platform is well suited to the study of E3 ligases and the effects of modulating E3 ligases on cellular phenotypes. DELPhe can be utilized to identify novel small molecules that bind E3 ligases and to optimize small molecules for a specific activity profile.
Unique advantages of E3 ligase manipulation for first-in-class therapeutics:
- Degradation profiles of E3 ligases can be manipulated in a tunable manner by small molecules
- Transcription factors become accessible to small molecule manipulation via induced degradation
- Both target-specific and beneficial pleiotropic effects can be exploited through phenotypic screens