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

Nature Medicine volume 4, pages 1293–1301 (1998)Cite this article

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.

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Figure 1: Model of antagonism of the calcineurin signaling pathway mediated by FK506 and cyclosporin A (CsA).
Figure 2: Expression profiles from FK506-treated wild-type (wt) cells and a calcineurin-disruption mutant strain share a genome-wide correlation.
Figure 3: Expression profiles from a his3 mutant strain and wild-type (wt) cells treated with 3-AT share a genome-wide correlation.
Figure 4: Treatment of the his3 mutant strain with 3-AT shows nearly complete loss of 3-AT signature.
Figure 5: Response of FK506 and CsA signature genes in strains with deletions in different genes.
Figure 6: Response of FK506 signature genes in strains with deletions in different genes.

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Acknowledgements

The authors thank all the members of Rosetta for their contributions to this work. We thank P. Linsley, D. Shoemaker and A. Murray for critical reading of the manuscript, and M. Cyert for providing yeast strains. Work done at Stanford was supported in part by the Howard Hughes Medical Institute, and by a grant to P.O.B from the NHGRI. P.O.B is an assistant investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Rosetta Inpharmatics, 12040 115th Avenue NE, Kirkland, 98034, Washington, USA

    Matthew J. Marton, Holly A. Bennett, Michael R. Meyer, Christopher J. Roberts, Roland Stoughton, Julja Burchard, David Slade, Hongyue Dai, Douglas E. Bassett Jr. & Stephen H. Friend

  2. Department of Biochemistry, Stanford University School of Medicine, Howard Hughes Medical Institute, Stanford, 94305-5428, California, USA

    Joseph L. DeRisi, Vishwanath R. Iyer & Patrick O. Brown

  3. Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Seattle, 98109, Washington, USA

    Leland H. Hartwell

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Correspondence to Stephen H. Friend.

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Marton, M., DeRisi, J., Bennett, H. et al. Drug target validation and identification of secondary drug target effects using DNA microarrays. Nat Med 4, 1293–1301 (1998). https://doi.org/10.1038/3282

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