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 muliplex phenotypic analysis only available by cell-based screening.
The key to our DELPhe platform is miniaturization. We are able to screen DNA- encoded small molecule libraries in picoliter to nanoliter volumes. Our innovations enable both cell-based and biochemical assays and will redefine high-throughput screening. We are leveraging our DELPhe technology to develop novel small molecule modulators of E3 ligases to uncover new therapeutic biology.
Experiments are performed in picowells with a signal 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 a small molecule, so it 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 screen
- Picowell format enables assays where reagent quantities are limitng
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.
Targeting E3 ligases enables the selective modulation of protein levels in the cell, including the degradation of specific protein targets. Plexium employs DELPhe to obtain a broad view on the cellular response to E3 ligase modulation by a small molecule, profiling millions of small molecules in a single experiment. Assays can be functional or phenotypic or designed for a specific target. These insights into the activity of each small molecule across multiple biologic measures should facilitate the optimal selection of therapeutic candidates for clinical testing and improved profiles of resulting therapeutics.
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