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An integrated platform of genomic assays reveals small-molecule bioactivities

Nature Chemical Biology volume 4, pages 498–506 (2008)Cite this article

A Corrigendum to this article was published on 01 October 2008

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Abstract

Bioactive compounds are widely used to modulate protein function and can serve as important leads for drug development. Identifying the in vivo targets of these compounds remains a challenge. Using yeast, we integrated three genome-wide gene-dosage assays to measure the effect of small molecules in vivo. A single TAG microarray was used to resolve the fitness of strains derived from pools of (i) homozygous deletion mutants, (ii) heterozygous deletion mutants and (iii) genomic library transformants. We demonstrated, with eight diverse reference compounds, that integration of these three chemogenomic profiles improves the sensitivity and specificity of small-molecule target identification. We further dissected the mechanism of action of two protein phosphatase inhibitors and in the process developed a framework for the rational design of multidrug combinations to sensitize cells with specific genotypes more effectively. Finally, we applied this platform to 188 novel synthetic chemical compounds and identified both potential targets and structure-activity relationships.

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Figure 1: An integrated chemogenomics screening platform.
Figure 2: Data integration improves small-molecule target prediction.
Figure 3: Cantharidin and calyculin A have distinct effects in vivo.
Figure 4: Mechanistic insights into drug interactions.
Figure 5: Characterization of new bioactive compounds.
Figure 6: Correlation of chemogenomic profiles with compound structure similarity.

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  • 17 September 2008

    In the version of this article initially published, there was a space missing in the author name Robert P St Onge. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank K. Tatchell (Louisiana State University) for sharing the glc-7 alleles and M. Cyert (Stanford University) for providing the S. cerevisiae genomic library. We thank H. Ng and S. Lockey for critically reading the manuscript and members of the chemogenomics lab at the Stanford Genome Technology Center for discussions. S.H. is supported by a graduate fellowship from the Agency for Science Technology and Research (Singapore). R.P.S. was supported by a postdoctoral fellowship from the Canadian Institutes of Health Research. K.M.S. and R.W.D. are supported by grants from the US National Institutes of Health; G.G. and C.N. are supported by grants from the US National Institutes of Health and the Canadian Institutes of Health Research (MOP-81340 to G.G. and MOP-84305 to C.N.).

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Authors and Affiliations

  1. Department of Genetics, Stanford University, Mail Stop-5120, Palo Alto, 94305, California, USA

    Shawn Hoon & Ronald W Davis

  2. Stanford Genome Technology Center, 855 California Avenue, Palo Alto, 94304, California, USA

    Shawn Hoon, Sundari Suresh, Molly Miranda, Eula Fung, Michael Proctor, Ronald W Davis & Robert P St Onge

  3. Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, M5S1A8, Ontario, Canada

    Andrew M Smith, Guri Giaever & Corey Nislow

  4. Banting and Best Department of Medical Research, University of Toronto, 112 College Street, Toronto, M5S3E1, Ontario, Canada

    Andrew M Smith, Iain M Wallace & Corey Nislow

  5. Donnelly Centre for Cellular and Biomedical Research, University of Toronto, 160 College Street, Toronto, M5S3E1, Ontario, Canada

    Andrew M Smith, Guri Giaever & Corey Nislow

  6. Department of Molecular Pharmacology, University of California, 600 16th Street, MC 2280, San Francisco, 94158-2280, California, USA

    Kevan M Shokat & Chao Zhang

  7. Department of Pharmaceutical Sciences, University of Toronto, 144 College Street, Toronto, M5S3M2, Ontario, Canada

    Guri Giaever

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Contributions

C.N., R.P.S. and S.H. designed the study, analyzed the data and wrote the paper; S.H. and R.P.S. did the experiments. G.G. analyzed the data and helped write the paper. A.S. did the glc7 allele analysis; I.M.W. did the cheminformatic analysis. M.P. designed the robotic assay platform; E.F. designed the database infrastructure. K.M.S. and C.Z. designed the cdc28-as experiment. R.W.D. provided valuable advice. M.M. and S.S. helped with genome-wide screens.

Corresponding authors

Correspondence to Robert P St Onge or Corey Nislow.

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Supplementary Figures 1–7, Supplementary Table 1 and Supplementary Methods (PDF 4803 kb)

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Hoon, S., M Smith, A., Wallace, I. et al. An integrated platform of genomic assays reveals small-molecule bioactivities. Nat Chem Biol 4, 498–506 (2008). https://doi.org/10.1038/nchembio.100

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