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Science 24 July 1998:
Vol. 281. no. 5376, pp. 533 - 538
DOI: 10.1126/science.281.5376.533
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Reports

Exploiting Chemical Libraries, Structure, and Genomics in the Search for Kinase Inhibitors

Nathanael S. Gray, Lisa Wodicka, Andy-Mark W. H. Thunnissen, Thea C. Norman, Soojin Kwon, F. Hernan Espinoza, David O. Morgan, Georjana Barnes, Sophie LeClerc, Laurent Meijer, Sung-Hou Kim, David J. Lockhart, Peter G. Schultz *

Selective protein kinase inhibitors were developed on the basis of the unexpected binding mode of 2,6,9-trisubstituted purines to the adenosine triphosphate-binding site of the human cyclin-dependent kinase 2 (CDK2). By iterating chemical library synthesis and biological screening, potent inhibitors of the human CDK2-cyclin A kinase complex and of Saccharomyces cerevisiae Cdc28p were identified. The structural basis for the binding affinity and selectivity was determined by analysis of a three-dimensional crystal structure of a CDK2-inhibitor complex. The cellular effects of these compounds were characterized in mammalian cells and yeast. In the latter case the effects were characterized on a genome-wide scale by monitoring changes in messenger RNA levels in treated cells with high-density oligonucleotide probe arrays. Purine libraries could provide useful tools for analyzing a variety of signaling and regulatory pathways and may lead to the development of new therapeutics.

N. S. Gray, T. C. Norman, S. Kwon, P. G. Schultz, Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA. L. Wodicka and D. J. Lockhart, Affymetrix, 3380 Central Expressway, Santa Clara, CA 95051, USA. A.-M. W. H. Thunnissen and S.-H. Kim, Lawrence Berkeley National Laboratory and Department of Chemistry, University of California, Berkeley, CA 94720, USA. F. Hernan Espinoza and D. O. Morgan, Department of Physiology, University of California, San Francisco, CA 94143-0444, USA. G. Barnes, Department of Molecular and Cellular Biology, University of California, Berkeley, CA 94720, USA. S. LeClerc and L. Meijer, CNRS, Station Biologique, 29682 Roscoff, France.
*   To whom correspondence should be addressed.

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P. Kapahi, T. Takahashi, G. Natoli, S. R. Adams, Y. Chen, R. Y. Tsien, and M. Karin (2000)
J. Biol. Chem. 275, 36062-36066
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Strength of the Calpha H{middle dot}{middle dot}O Hydrogen Bond of Amino Acid Residues.
S. Scheiner, T. Kar, and Y. Gu (2001)
J. Biol. Chem. 276, 9832-9837
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Crystallographic Approach to Identification of Cyclin-dependent Kinase 4 (CDK4)-specific Inhibitors by Using CDK4 Mimic CDK2 Protein.
M. Ikuta, K. Kamata, K. Fukasawa, T. Honma, T. Machida, H. Hirai, I. Suzuki-Takahashi, T. Hayama, and S. Nishimura (2001)
J. Biol. Chem. 276, 27548-27554
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Flavopiridol Inactivates P-TEFb and Blocks Most RNA Polymerase II Transcription in Vivo.
S.-H. Chao and D. H. Price (2001)
J. Biol. Chem. 276, 31793-31799
   Abstract »    Full Text »    PDF »


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