An integrative biology approach for analysis of drug action in models of human vascular inflammation.
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-alpha 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.
Kunkel
Eric J
EJ
BioSeek, Inc., Burlingame, California 94010, USA.
Dea
Marlene
M
Ebens
Allen
A
Hytopoulos
Evangelos
E
Melrose
Jennifer
J
Nguyen
Dat
D
Ota
Ken S
KS
Plavec
Ivan
I
Wang
Yuker
Y
Watson
Susan R
SR
Butcher
Eugene C
EC
Berg
Ellen L
EL
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000037:antagonists & inhibitors; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000145:classification; D034741:RNA, Small Interfering / Q000494:pharmacology; D014162:Transfection; D014471:Umbilical Veins; D014657:Vasculitis / Q000188:drug therapy*
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D004364:Pharmaceutical Preparations; D034741:RNA, Small Interfering