Drug target validation and identification of secondary drug target effects using DNA microarrays

Matthew J. Marton, Joseph L. Derisi, Holly A. Bennett, Vishwanath R. Iyer, Michael R. Meyer, Christopher J. Roberts, Roland Stoughton, Julja Burchard, David Slade, Hongyue Dai, Douglas E. Bassett, Leland H. Hartwell, Patrick O. Brown, Stephen H. Friend

Research output: Contribution to journalArticle

569 Scopus citations

Abstract

We describe here a method for drug target validation and identification of secondary drug target effects based on genome-wide gene expression patterns. The method is demonstrated by several experiments, including treatment of yeast mutant strains defective in calcineurin, immunophilins or other genes with the immunosuppressants cyclosporin A or FK506. Presence or absence of the characteristic drug 'signature' pattern of altered gene expression in drug-treated cells with a mutation in the gene encoding a putative target established whether that target was required to generate the drug signature. Drug dependent effects were seen in 'targetless' cells, showing that FK506 affects additional pathways independent of calcineurin and the immunophilins. The described method permits the direct confirmation of drug targets and recognition of drug-dependent changes in gene expression that are modulated through pathways distinct from the drug's intended target. Such a method may prove useful in improving the efficiency of drug development programs.

Original languageEnglish (US)
Pages (from-to)1293-1301
Number of pages9
JournalNature Medicine
Volume4
Issue number11
DOIs
StatePublished - Nov 1 1998
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Marton, M. J., Derisi, J. L., Bennett, H. A., Iyer, V. R., Meyer, M. R., Roberts, C. J., Stoughton, R., Burchard, J., Slade, D., Dai, H., Bassett, D. E., Hartwell, L. H., Brown, P. O., & Friend, S. H. (1998). Drug target validation and identification of secondary drug target effects using DNA microarrays. Nature Medicine, 4(11), 1293-1301. https://doi.org/10.1038/3282