Fig. 2.
Schema of the drug discovery and development pipeline. The initial stages of the pipeline focus on the discovery and validation of newly identified disease-associated drug targets. Target validation is carried out using in vitro and in vivo approaches to confirm the relevance of the target in the disease being studied. This is followed by the identification of lead compounds through high-throughput or focused screens of chemical libraries or of naturally occurring molecules, or by structure-based rational drug design. The next stage is lead optimization, where the identified compound is subjected to chemical modifications to improve its pharmacological properties. Optimized lead compounds are then carried forward into preclinical testing, where pharmacology, toxicity and efficacy are assessed. Preclinical testing can occur in vitro, in 2- or 3-dimensional cell culture assays, or in vivo, in either xenografts or animal models, including genetically engineered mouse models (GEMMs). Promising therapies identified here are taken forward into the clinic. Preclinical models thus provide a bridge to the clinic, and are a requisite part of the drug development pipeline. For more detailed descriptions of the different stages of this pipeline, we refer readers to several recent reviews (Herter-Sprie et al., 2013; Hughes et al., 2011; Kamb et al., 2007; Kenakin, 2003; Pritchard et al., 2003).