Drugs fail in clinical studies most often from lack of efficacy or unexpected toxicities. These failures result from an inadequate understanding of drug action and follow, in part, from our dependence on drug discovery technologies that do not take into account the complexity of human disease biology. Biological systems exhibit many features of complex engineering systems, including modularity, redundancy, robustness, and emergent properties. Addressing these features has contributed to the successful design of an improved biological assay technology for inflammation drug discovery. This approach, termed Biologically Multiplexed Activity Profiling (BioMAP), involves the statistical analysis of protein datasets generated from novel complex primary human cell-based assay systems. Compound profiling in these systems has revealed that a surprisingly large number of biological mechanisms can be detected and distinguished. Features of these assays relevant to the behaviour of complex systems are described.
References
-
-
1)
-
E.C. Butcher ,
E.L. Berg ,
E.J. Kunkel
.
Systems biology in drug discovery.
Nat. Biotechnol.
,
10 ,
1253 -
1259
-
2)
-
E.J. Kunkel ,
I. Plavec ,
D. Nguyen ,
J. Melrose ,
E.S. Rosler ,
L.T. Kao ,
Y. Wang ,
E. Hytopoulos ,
A.C. Bishop ,
R. Bateman ,
K.M. Shokat ,
E.C. Butcher ,
E.L. Berg
.
Rapid structure-activity and selectivity analysis of kinase inhibitors by BioMAP analysis in complex human primary cell-based models.
Assay Drug Dev. Technol.
,
4 ,
431 -
441
-
3)
-
J. Mestas ,
C. Hughes
.
Of mice and men: differences between mouse and human immunology.
J. Immunol.
,
2731 -
2738
-
4)
-
E.L. Berg ,
E. Hytopoulos ,
I. Plavec ,
E.J. Kunkel
.
Approaches to the analysis of cell signaling networks and their application in drug discovery.
Curr. Opin. Drug Discov. Devel.
,
1 ,
107 -
114
-
5)
-
H. Kitano ,
H. Kitano
.
(2001)
Systems biology: toward system-level understanding of biological systems, Foundations of systems biology.
-
6)
-
D. Kim ,
T. Aizawa ,
H. Wei ,
X. Pi ,
S.D. Rybalkin ,
B.C. Berk ,
C. Yan
.
Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: a mechanism by which angiotensin II antagonizes cGMP signaling.
J. Mol. Cell Cardiol.
,
1 ,
175 -
184
-
7)
-
I. Plavec ,
O. Sirenko ,
S. Privat ,
Y. Wang ,
M. Dajee ,
J. Melrose ,
B. Nakao ,
E. Hytopoulos ,
E.L. Berg ,
E.C. Butcher
.
Method for analyzing signaling networks in complex cellular systems.
Proc. Natl. Acad. Sci. USA
,
5 ,
1223 -
1228
-
8)
-
M.E. Csete ,
J.C. Doyle
.
Reverse engineering of biological complexity.
Science
,
1664 -
1669
-
9)
-
E.C. Butcher
.
Can cell systems biology rescue drug discovery?.
Nat. Rev. Drug Discov.
,
6 ,
461 -
467
-
10)
-
J.D. Storey ,
R. Tibshirani
.
Statistical significance for genomewide studies.
Proc. Natl. Acad. Sci. USA
,
16 ,
9440 -
9445
-
11)
-
E.J. Kunkel ,
M. Dea ,
A. Ebens ,
E. Hytopoulos ,
J. Melrose ,
D. Nguyen ,
K.S. Ota ,
I. Plavec ,
Y. Wang ,
S.R. Watson ,
E.C. Butcher ,
E.L. Berg
.
An integrative biology approach for analysis of drug action in models of human vascular inflammation.
FASEB J.
,
11 ,
1279 -
1281
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