(1257-B) DELs to NanoBRET Probes: Enabling Cell-Active Target Engagement
Monday, February 5, 2024
2:00 PM – 3:00 PM EST
Location: Exhibit Halls AB
Abstract: Since its discovery, DNA encoded library (DEL) technology has evolved into an essential tool to rapidly identify novel small molecules for early-stage drug discovery. DEL technology utilizes a unique design which connects structural information with DNA barcodes. This design has enabled rapid affinity-based screening against purifiable protein targets and has allowed for exploration of chemical diversity at a scale not possible with traditional small molecule libraries. Herein, we describe a workflow that exploits the bifunctional nature of DEL ligands as an approach generate probes for live cell target engagement studies. NanoBRET is a proximity-based assay that measures compound target engagement using bioluminescence resonance energy transfer (BRET) technology. Proof of concept of our workflow was established by performing a DEL screen against aurora kinase A and successfully converting aurora DEL ligands into cell-active NanoBRETTM probes. Aurora kinase NanoBRETTM probes then enabled the validation and hit prioritization of the initial chemical series identified during the DEL selection. We also evaluated the effective repurposing of pre-existing DEL screen data (BRD4 and IDO1) and found suitable leads for NanoBRETTM probe development. Our findings support the use of DEL workflows as an engine to create cell-active NanoBRETTM probes independent of structure or compound SAR. The combination of DEL and NanoBRETTM technology should accelerate hit-to-lead studies in a live cell setting.