The Safety Relevance and Interpretation of Compound Off‐target Interactions
Eric A.G. Blomme, Jonathon R. Green, Prathap Kumar S. Mahalingaiah, Terry R. Van Vleet, Andy H. Vo · 2024
This chapter reviews the potential safety challenges posed by off-target interactions of experimental therapeutic molecules, screening approaches to mitigate the risks, and interpretation of screening data in the context of safety. Safety is the primary concern of lack of selectivity of experimental molecules, as modulation of the activity of off-targets is often associated with adverse side effects. This issue is most prevalent for small-molecule drugs and is affected by multiple factors such as physicochemical properties or the nature of the off-targets. A discussion of off-target interactions for both small and large molecules, as well as a high-level review of options for in vitro and in silico screens and interpretation considerations, is presented. Some specific examples of off-targets included in screens are discussed to illustrate the considerations that can be applied to other targets.