2. Academic Validation
  3. DELs enable the development of BRET probes for target engagement studies in cells

DELs enable the development of BRET probes for target engagement studies in cells

  • Cell Chem Biol. 2023 Aug 17;30(8):987-998.e24. doi: 10.1016/j.chembiol.2023.06.019.
Kelly A Teske 1,  Wenji Su 2,  Cesear R Corona 3,  Jing Wen 2,  Jason Deng 2,  Yan Ping 2,  Zaihong Zhang 2,  Qi Zhang 2,  Jennifer Wilkinson 1,  Michael T Beck 1,  Kendra R Nealey 1,  James D Vasta 1,  Mei Cong 1,  Poncho L Meisenheimer 1,  Letian Kuai 4,  Matthew B Robers 5
Affiliations

Affiliations

  • 1 Promega Corporation, 2800 Woods Hollow Road, Fitchburg, WI 53711, USA.
  • 2 WuXi AppTec Headquarters, 288 Fute Shong Road Waigaopqiao Free Trade Zone, Pudong District, Shanghai 200131, China.
  • 3 Promega Biosciences Incorporated, 277 Granada Drive, San Luis Obispo, CA 93401, USA.
  • 4 WuXi AppTec Headquarters, 288 Fute Shong Road Waigaopqiao Free Trade Zone, Pudong District, Shanghai 200131, China. Electronic address: [email protected].
  • 5 Promega Corporation, 2800 Woods Hollow Road, Fitchburg, WI 53711, USA. Electronic address: [email protected].
PMID: 37490918 DOI: 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.

Keywords

Aurora; BRD4; BRET; DEL; DNA-encoded library; IDO1; NanoBRET; NanoLuc; Nluc; target engagement.

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