RASPELD to Perform High‐End Screening in an Academic Environment toward the Development of Cancer Therapeutics

• Published in: ChemMedChem Vol. 13; no. 19; pp. 2065 - 2072
• Main Authors: Wolle, Patrik, Weisner, Jörn, Keul, Marina, Landel, Ina, Lategahn, Jonas, Rauh, Daniel
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 08.10.2018
• Subjects: Cancer; Drug development; drug discovery; Epidermal growth factor; Epidermal growth factor receptors; Growth factors; hit validation; initial screen; medicinal chemistry; Mutants; Optimization; Organic chemistry; Resistant mutant; Screening; hit validation; cancer; initial screen; drug discovery; medicinal chemistry
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201800477

The identification of compounds for dissecting biological functions and the development of novel drug molecules are central tasks that often require screening campaigns. However, the required architecture is cost‐ and time‐intensive. Herein we describe the devices and technologies that comprise a Robotics‐Assisted Screening Platform for Efficient Ligand Discovery (RASPELD), which we set up in an academic laboratory. RASPELD provides semi‐automated high‐end screening, and it can be maintained by graduate students. We demonstrate its successful application in biochemical and cellular screens for the identification and validation of bioactive chemical entities as candidate cancer‐relevant inhibitors. Specifically, we examined the interaction between a transcription factor, Nrf2, and its key regulator, Keap1. We also examined drug‐resistant mutants of the epidermal growth factor receptor (EGFR). Screening campaigns with more than 30 000 compounds were performed in a reasonable period of time. We identified the molecule RSL6586 as a starting point for hit optimization, which is currently ongoing. Hits on the big screen: We describe the setup of the academic screening platform RASPELD (Robotics‐Assisted Screening Platform for Efficient Ligand Discovery). It enables high‐end compound screening capacity that we applied in both biochemical and cellular screening initiatives. We present the identified molecule RSL6586 with anticancer activities as a starting point for further hit optimization.