[DOT 2021] Expanding the Toolbox of E3scan Ligand Binding Assay Platform for Targeted Protein Degradation
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- DOT 2021
Targeted protein degradation (TPD) utilizes small molecules to hijack the cellular degradation machinery through recruitment of E3 ubiquitin ligases to proteins of interest. This induces the ubiquitin-dependent degradation of these target proteins. TPD is of interest in drug development as it can address previously considered undruggable targets (80% of the human proteome) that cannot be inhibited with traditional small molecule inhibitors, such as scaffold proteins and transcription factors. Two decades have passed since the introduction of the first PROTAC® degrader; however, degrader discovery and optimization remains an empirically slow process. The majority of degraders that are in clinical trials recruit the CRBN or VHL E3 ligases to ubiquitinate a protein of interest. Recent studies suggest that varying the recruited E3 ligase can influence the range of target proteins degraded. With the potential to add about half of the 600 human E3 ligases to the TPD toolbox, which are involved in the ubiquitin-proteasome system, the degradable target space can significantly expand. To help accelerate the TPD field in drug discovery, Eurofins Discovery is diversifying its novel E3scan™ ligand-binding platform with additional E3 ligase target assays. Here, we present assay validation data for E3 ligases that have not yet been utilized in TPD and for which no small molecule ligands have been previously reported. In addition, we present E3scan assays for individual substrate domains to screen for E3 ligase substrate selectivity. In sum, we show that our novel E3scan platform enables accelerated screening and SAR analysis in the TPD drug discovery field, with rapid turnaround times for discovery library screens (20 business day TAT) and weekly SAR (5 business day TAT), and the largest assay panel available on a single technology platform.