Elucidating Target Biology and Drug Mechanism of Action Across Human Cell‐Based Model Systems

Drug discovery operating models must evolve in order to address high attrition rates during late‐stage drug development and clinical application of new therapies resulting from poor efficacy. In this chapter we outline several recent state‐of‐the‐art advances in functional biology tools and methodology and how they combine with new developments in human cell‐based disease models to enable a more in‐depth and unbiased evaluation of target biology under relevant tissue and disease context. We describe how new phenotypic and pathway profiling technology platforms such as gene editing, human stem cells, high‐content imaging, next‐generation sequencing, and antibody‐based proteomics complement and combine with other disciplines including bioinformatics, chemoinformatics, chemical proteomics, and emerging computational methods to build a more clinically predictive and informative analysis of novel therapeutic targets and drug mechanism of action. These new technology advances are converging to enable more empirical, evidence‐led models for functional validation of novel therapeutic targets and candidate drugs under appropriate disease context.