title: Chemical genomic profiling to identify intracellular targets of a multiplex kinase inhibitor.
abstract: The identification of the kinase or kinases targeted by protein kinase inhibitors is a critical challenge in validating their use as therapeutic agents or molecular probes. Here, to address this problem, we describe a chemical genomics strategy that uses a direct comparison between microarray transcriptional signatures elicited by an inhibitor of unknown specificity and those elicited by highly specific pharmacological inhibition of engineered candidate kinase targets. By using this approach, we have identified two cyclin-dependent kinases, Cdk1 and Pho85, as the targets of the inhibitor GW400426 in Saccharomyces cerevisiae. We demonstrate that simultaneous inhibition of Cdk1 and Pho85, and not inhibition of either kinase alone, by GW400426 controls the expression of specific transcripts involved in polarized cell growth, thus revealing a cellular process that is uniquely sensitive to the multiplex inhibition of these two kinases. Our results suggest that the cellular responses induced by multiplex protein kinase inhibitors may be an emergent property that cannot be understood fully by considering only the sum of individual inhibitor-kinase interactions.
authors.affiliation: Computational, Analytical, and Structural Sciences, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Kung
authors.forename: Denise M
authors.initials: DM
authors.lastname: Kenski
authors.forename: Scott H
authors.initials: SH
authors.lastname: Dickerson
authors.forename: Russell W
authors.initials: RW
authors.lastname: Howson
authors.forename: Lee F
authors.initials: LF
authors.lastname: Kuyper
authors.forename: Hiten D
authors.initials: HD
authors.lastname: Madhani
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
mesh_terms: D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D020869:Gene Expression Profiling; D023281:Genomics; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D029701:Saccharomyces cerevisiae Proteins; D016203:CDC2 Protein Kinase; D018844:Cyclin-Dependent Kinases; C058605:PHO85 protein, S cerevisiae
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