Abstract

The main approaches for compound structure-activity relationship (SAR) screening are to use bespoke biochemical assays or assays in cell lines engineered to express the target of interest. A more advanced approach is to use primary cells expressing targets endogenously, situated closer to the disease phenotype of interest.

Primary cell assays can help identify compounds that fail to act or act with reduced potency on the target, due to the more physiological environment in primary cells. However, cost of primary cells and their flaws in terms of ease of use and suitability for certain read-outs limits their usability for compound SAR screening.

We therefore set out to develop an assay for compound screening in primary cells that covers as broad of a range of targets across different cell types, with the aim of cutting down assay development time and cost, as well as to provide more projects with a ready-to-use primary cell screening assay. This led to the combination of the heterogenous peripheral blood mononuclear cells (PBMCs) with the Cell Painting imaging read-out.