A practical guide to secondary pharmacology in drug discovery

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Secondary pharmacological profiling is increasingly applied in pharmaceutical drug discovery to address unwanted pharmacological side effects of drug candidates before entering the clinic. Regulators, drug makers and patients share a demand for deep characterization of secondary pharmacology effects of novel drugs and their metabolites. The scope of such profiling has therefore expanded substantially in the past two decades, leading to the implementation of broad in silico profiling methods and focused in vitro off-target screening panels, to identify liabilities, but also opportunities, as early as possible. The pharmaceutical industry applies such panels at all stages of drug discovery routinely up to early development. Nevertheless, target composition, screening technologies, assay formats, interpretation and scheduling of panels can vary significantly between companies in the absence of dedicated guidelines. To contribute towards best practices in secondary pharmacology profiling, this review aims to summarize the state-of-the art in this field. Considerations are discussed with respect to panel design, screening strategy, implementation and interpretation of the data, including regulatory perspectives. The cascaded, or integrated, use of in silico and off-target profiling allows to exploit synergies for comprehensive safety assessment of drug candidates.