An efficient rapid system for profiling the cellular activities of molecular libraries.
Rapid quantitative methods for characterizing small molecules, peptides, proteins, or RNAs in a broad array of cellular assays would allow one to discover new biological activities associated with these molecules and also provide a more comprehensive profile of drug candidates early in the drug development process. Here we describe a robotic system, termed the automated compound profiler, capable of both propagating a large number of cell lines in parallel and assaying large collections of molecules simultaneously against a matrix of cellular assays in a highly reproducible manner. To illustrate its utility, we have characterized a set of 1,400 kinase inhibitors in a panel of 35 activated tyrosine-kinase-dependent cellular assays in dose-response format in a single experiment. Analysis of the resulting multidimensional dataset revealed subclusters of both inhibitors and kinases with closely correlated activities. The approach also identified activities for the p38 inhibitor BIRB796 and the dual src/abl inhibitor BMS-354825 and exposed the expected side activities for Glivec/STI571, including cellular inhibition of c-kit and platelet-derived growth factor receptor. This methodology provides a powerful tool for unraveling the cellular biology and molecular pharmacology of both naturally occurring and synthetic chemical diversity.
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Jonathan S
JS
Melnick
Jeff
J
Janes
Sungjoon
S
Kim
Jim Y
JY
Chang
Daniel G
DG
Sipes
Drew
D
Gunderson
Laura
L
Jarnes
Jason T
JT
Matzen
Michael E
ME
Garcia
Tami L
TL
Hood
Ronak
R
Beigi
Gang
G
Xia
Richard A
RA
Harig
Hayk
H
Asatryan
S Frank
SF
Yan
Yingyao
Y
Zhou
Xiang-Ju
XJ
Gu
Alham
A
Saadat
Vicki
V
Zhou
Frederick J
FJ
King
Christopher M
CM
Shaw
Andrew I
AI
Su
Robert
R
Downs
Nathanael S
NS
Gray
Peter G
PG
Schultz
Markus
M
Warmuth
Jeremy S
JS
Caldwell
D000818:Animals; D001331:Automation; D002460:Cell Line; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical / Q000379:methods; D051379:Mice; D010770:Phosphotransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015203:Reproducibility of Results; D012371:Robotics / Q000379:methods*; D013329:Structure-Activity Relationship; D013997:Time Factors
D047428:Protein Kinase Inhibitors; D010770:Phosphotransferases