[An efficient rapid system for profiling the cellular activities of molecular libraries]
>>Published online before print February 21, 2006
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0511292103
OPEN ACCESS ARTICLE
An efficient rapid system for profiling the cellular activities of molecular libraries
Jonathan S. Melnick *, Jeff Janes , Sungjoon Kim , Jim Y. Chang , Daniel G. Sipes , Drew Gunderson , Laura Jarnes , Jason T. Matzen , Michael E. Garcia , Tami L. Hood , Ronak Beigi , Gang Xia , Richard A. Harig , Hayk Asatryan , S. Frank Yan , Yingyao Zhou , Xiang-Ju Gu , Alham Saadat , Vicki Zhou , Frederick J. King , Christopher M. Shaw , Andrew I. Su , Robert Downs , Nathanael S. Gray , Peter G. Schultz *, Markus Warmuth , and Jeremy S. Caldwell
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121; and *The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037
Contributed by Peter G. Schultz, December 29, 2005
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.<<
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