Using Phenotypic Screening to Uncover the Full Potential of Polypharmacology
Arsenio Nueda · 2024
Phenotypic screening and, more generally, phenotypic drug discovery (PDD) have proven their potential to capture novel polypharmacology-based mechanisms of action (MoA) that, in many cases, would be too complex to engineer both from a chemistry and a biology perspective. Phenotypic screening queries the functional interface between disease model systems and libraries of chemical or biological perturbagens to identify active hits modulating disease-relevant phenotypic endpoints. For chemical perturbagens, hits can be optimized and profiled to explore their on-target and dispensable off-target signatures and MoA. In this chapter, the fundamental concepts that are key to capturing and optimizing phenotypic screening-derived polypharmacology are described from a practical standpoint using specific examples. Additional insight is provided on how PDD can take advantage of the toolbox of increasingly translational disease models combined with advanced omics profiling to support the progression of phenotypic hits with a multi-target MoA from screening to the preclinical drug candidate stage.