Biology calls the targets: combining RNAi and disease biology

Target-based drug discovery starts with the identification of target genes and their respective protein products (associated with or controlling a disease-relevant phenotype) that, when inhibited or activated, ameliorate the associated disease. To identify disease-relevant genes, robust tools are needed to allow biology-driven target discovery and validation. Moreover, insight into the underlying biology of a disease is essential to model a disease in vitro. Key questions are: What are the disease hallmarks? What are, from a biological point of view, the best points for therapeutic intervention? How can scientists model these points in vitro? What is the desired target profile? The closer the cellular models resemble the disease situation, the better the target profile will be. The profile is the set of biological data needed to accept the target for drug discovery. In this review, a focused approach for target discovery and validation is presented. Arrayed adenoviral siRNA libraries and disease-based cellular models are used that generate high-quality and functionally validated targets.