VeloceGenomics: an accelerated in vivo drug discovery approach to rapidly predict the biologic, drug-like activity of compounds, proteins, or genes

• Published in: Pharmaceutical research 2005-10, Vol.22 (10), p.1597-1613
• Main Authors: Papoian, Ruben, Scherer, Andreas, Saulnier, Muriel, Staedtler, Frank, Cordier, André, Legay, Francois, Maurer, Gerard, Staeheli, Joerg, Vonderscher, Jacky, Chibout, Salah-Dine
• Format: Article
• Language: English
• Subjects: Animals; Cytokines; Drug Design; Female; Gene expression; Gene Expression - drug effects; Insulin; Insulin-like growth factors; Interleukin-6 - pharmacology; Kinases; Leukemia; Leukemia Inhibitory Factor; Macaca fascicularis; Male; Pharmaceutical industry; Pharmacogenetics - methods; Predictive Value of Tests; Protein Array Analysis; Proteins; Proteins - genetics; Proteins - physiology; R&D; Research & development; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Somatostatin - analogs & derivatives; Somatostatin - pharmacology; Structure-Activity Relationship
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-005-6809-8

The aim of this study is to test the predictive power of in vivo multiorgan RNA expression profiling in identifying the biologic activity of molecules. Animals were treated with compound A or B. At the end of the treatment period, in vivo multiorgan microarray-based gene expression data were collected. Investigators masked to the identity of the compounds analyzed the transcriptome signatures to define the molecular pathways affected by treatment and to hypothesize the biologic activity and potential therapeutic indications of the blinded compounds. For compound A, G-protein-coupled receptors and factors associated with cell growth were affected-growth hormone/insulin-like growth factor-1, glucagon/insulin axes, and general somatomedin-like activity. Deblinding showed the compound to be a somatostatin analog, SOM230, confirming the accuracy of the predicted biologic activity. For compound B, components of the inflammatory cascade potentially mediated by lipopolysaccharide, tumor necrosis factor, or proinflammatory cytokines were affected. The gene expression signatures were most consistent with an interleukin-6 family activity. Deblinding revealed that compound B was leukemia inhibitory factor. VeloceGenomics is a strategy of coupling in vivo compound testing with genomic technologies. The process enables prediction of the mechanism of action and, coupled with other relevant data, prediction of the suitability of compounds for advancement in the drug development process.