Abstract

Drug discovery is undergoing a paradigm shift whereby the number of challenging targets entering the hit discovery pipeline is increasing exponentially. Often for these targets there are limited tool compounds available, and protein generation is challenging. As such, cellular high throughput (HT) screening is becoming more commonplace, however it presents additional challenges to high throughput assay development. Cell-based HT screening approaches are more complex in nature with a higher liability for false positives and require the generation of appropriate cell models, and increased deconvolution compared to biochemical approaches. Herein we developed and validated a 1536-well cell-based screening cascade for an exciting and challenging target, a transport protein referred to here as Target A. To achieve this, we utilized the latest technologies available in cell line generation and high dimensional experimentation (HDE) to deliver a highly robust assay format suitable for primary screening within 3 months of cell line availability, 6 months from proof-of-concept initiation.