An integrative biology approach for analysis of drug action in models of human vascular inflammation

• Published in: The FASEB journal Vol. 18; no. 11; pp. 1279 - 1281
• Main Authors: Kunkel, Eric J., Dea, Marlene, Ebens, Allen, Hytopoulos, Evangelos, Melrose, Jennifer, Nguyen, Dat, Ota, Ken S., Plavec, Ivan, Wang, Yuker, Watson, Susan R., Butcher, Eugene C., Berg, Ellen L.
• Format: Journal Article
• Language: English
• Published: United States Federation of American Societies for Experimental Biology 01-08-2004
• Subjects: adhesion; Anti-Inflammatory Agents - pharmacology; Cells, Cultured - drug effects; chemokine; Coculture Techniques; Cytokines - antagonists & inhibitors; Drug Design; Drug Evaluation, Preclinical - methods; Endothelial Cells - drug effects; endothelium; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay; Humans; Immunosuppressive Agents - pharmacology; leukocyte; Leukocytes, Mononuclear - drug effects; Models, Biological; Pharmaceutical Preparations - classification; RNA, Small Interfering - pharmacology; systems biology; Transfection; Umbilical Veins; Vasculitis - drug therapy
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.04-1538fje

ABSTRACT
Unexpected drug activities discovered during clinical testing establish the need for better characterization of compounds in human disease‐relevant conditions early in the discovery process. Here, we describe an approach to characterize drug function based on statistical analysis of protein expression datasets from multiple primary human cell‐based models of inflammatory disease. This approach, termed Biologically Multiplexed Activity Profiling (BioMAP), provides rapid characterization of drug function, including mechanism of action, secondary or off‐target activities, and insights into clinical phenomena. Using three model systems containing primary human endothelial cells and peripheral blood mononuclear cells in different environments relevant to vascular inflammation and immune activation, we show that BioMAP profiles detect and discriminate multiple functional drug classes, including glucocorticoids; TNF‐α antagonists; and inhibitors of HMG‐CoA reductase, calcineurin, IMPDH, PDE4, PI‐3 kinase, hsp90, and p38 MAPK, among others. The ability of cholesterol lowering HMG‐CoA reductase inhibitors (statins) to improve outcomes in rheumatic disease patients correlates with the activities of these compounds in our BioMAP assays. In addition, the activity profiles identified for the immunosuppressants mycophenolic acid, cyclosporin A, and FK‐506 provide a potential explanation for a reduced incidence of posttransplant cardiovascular disease in patients receiving mycophenolic acid. BioMAP profiling can allow integration of meaningful human biology into drug development programs.