Discovery of novel targets with high throughput RNA interference screening.
High throughput technologies have the potential to affect all aspects of drug discovery. Considerable attention is paid to high throughput screening (HTS) for small molecule lead compounds. The identification of the targets that enter those HTS campaigns had been driven by basic research until the advent of genomics level data acquisition such as sequencing and gene expression microarrays. Large-scale profiling approaches (e.g., microarrays, protein analysis by mass spectrometry, and metabolite profiling) can yield vast quantities of data and important information. However, these approaches usually require painstaking in silico analysis and low-throughput basic wet-lab research to identify the function of a gene and validate the gene product as a potential therapeutic drug target. Functional genomic screening offers the promise of direct identification of genes involved in phenotypes of interest. In this review, RNA interference (RNAi) mediated loss-of-function screens will be discussed and as well as their utility in target identification. Some of the genes identified in these screens should produce similar phenotypes if their gene products are antagonized with drugs. With a carefully chosen phenotype, an understanding of the biology of RNAi and appreciation of the limitations of RNAi screening, there is great potential for the discovery of new drug targets.
Kassner
Paul D
PD
Lead Discovery Department, Amgen Inc., South San Francisco, CA 94080, USA. pkassner@amgen.com
D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000235:genetics; D015203:Reproducibility of Results; D054852:Small Molecule Libraries; D046888:Tissue Array Analysis / Q000379:methods; D014162:Transfection
D012330:RNA, Double-Stranded; D054852:Small Molecule Libraries