Kelly A. Teske; Wenji Su; Cesear R. Corona; Jing Wen; Jason Deng; Yan Ping; Zaihong Zhang; Qi Zhang; Jennifer Wilkinson; Michael T. Beck; Kendra R. Nealey; James D. Vasta; Mei Cong; Poncho L. Meisenheimer; Letian Kuai; Matthew B. Robers
Cell Chem. Biolo., 2023, 30(8), 987-998
https://doi.org/10.1016/j.chembiol.2023.06.019

Abstract

DNA-encoded libraries (DELs) provide unmatched chemical diversity and starting points for novel drug modalities. Here, we describe a workflow that exploits the bifunctional attributes of DEL ligands as a platform to generate BRET probes for live cell target engagement studies. To establish proof of concept, we performed a DEL screen using aurora kinase A and successfully converted aurora DEL ligands as cell-active BRET probes. Aurora BRET probes enabled the validation and stratification of the chemical series identified from primary selection data. Furthermore, we have evaluated the effective repurposing of pre-existing DEL screen data to find suitable leads for BRET probe development. Our findings support the use of DEL workflows as an engine to create cell-active BRET probes independent of structure or compound SAR. The combination of DEL and BRET technology accelerates hit-to-lead studies in a live cell setting.