Rapid structure-activity and selectivity analysis of kinase inhibitors by BioMAP analysis in complex human primary cell-based models.
Rapid, quantitative methods for characterizing the biological activities of kinase inhibitors in complex human cell systems could allow the biological consequences of differential target selectivity to be monitored early in development, improving the selection of drug candidates. We have previously shown that Biologically Multiplexed Activity Profiling (BioMAP) permits rapid characterization of drug function based on statistical analysis of protein expression data sets from complex primary human cellbased models of disease biology. Here, using four such model systems containing primary human endothelial cells and peripheral blood mononuclear cells in which multiple signaling pathways relevant to inflammation and immune responses are simultaneously activated, we demonstrate that BioMAP analysis can detect and distinguish a wide range of inhibitors directed against different kinase targets. Using a panel of p38 mitogen-activated protein kinase antagonists as a test set, we show further that related compounds can be distinguished by unique features of the biological responses they induce in complex systems, and can be classified according to their induction of shared (on-target) and secondary activities. Statistical comparisons of quantitative BioMAP profiles and analysis of profile features allow correlation of induced biological effects with chemical structure and mapping of biological responses to chemical series or substituents on a common scaffold. Integration of automated BioMAP analysis for prioritization of hits and for structure-activity relationship studies may improve and accelerate the design and selection of optimal therapeutic candidates.
Kunkel
Eric J
EJ
BioSeek, Inc., Bingame, CA, USA.
Plavec
Ivan
I
Nguyen
Dat
D
Melrose
Jennifer
J
Rosler
Elen S
ES
Kao
Leon T
LT
Wang
Yuker
Y
Hytopoulos
Evangelos
E
Bishop
Anthony C
AC
Bateman
Raynard
R
Shokat
Kevan M
KM
Butcher
Eugene C
EC
Berg
Ellen L
EL
D000818:Animals; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D018274:Electroporation; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000032:analysis* / Q000737:chemistry*; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013329:Structure-Activity Relationship; D014162:Transfection
D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011494:Protein Kinases