Exploratory toxicology as an integrated part of drug discovery. Part I: Why and how

•Early hazard identification, reliable risk assessment and diligent risk avoidance strategies are essential.•We describe why toxicology should be an integrated discipline within the drug discovery process.•We focus on target safety assessment, identification of series without inherent safety risks, optimization on safety and profiling of candidates.•We discuss the safety areas to be addressed with screening during the discovery process. Toxicity and clinical safety have major impact on drug development success. Moving toxicological studies into earlier phases of the R&D chain prevents drug candidates with a safety risk from entering clinical development. However, to identify candidates without such risk, safety has to be designed actively. Therefore, we argue that toxicology should be fully integrated into the discovery process. We describe our strategy, including safety assessment of novel targets, selection of chemical series without inherent liabilities, designing out risk factors and profiling of candidates, and we discuss considerations regarding what to screen for. We aim to provide timely go/no-go decisions (fail early) and direction to the discovery teams, by steering away from safety risk (showing what will not fail).