Target Engagement Measures in Preclinical Drug Discovery: Theory, Methods, and Case Studies

Target engagement (TE) in drug discovery is generally defined as the interaction of ligands with their target biomolecules. Understanding TE allows research teams to design and interpret quality in vivo experiments, providing a more refined assessment of target validation. It can also orient teams toward delivering molecules that better enable clinical studies by focusing SAR efforts on the optimization of projected human performance characteristics. In this chapter, theoretical aspects of TE and its importance for addressing drug discovery issues like selectivity and the relationship of pharmacokinetics to pharmacodynamics are addressed. Methods to measure TE directly are reviewed along with a discussion of how to estimate TE based on pharmacokinetic data. The principles outlined within the chapter are then demonstrated by application to a theoretical drug discovery effort focused on validation of a novel protein target. Finally, two case studies are discussed in which application of these principles was used to optimize compounds toward desired human performance characteristics in one instance and to drive a target de-prioritization decision in another.