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High-Throughput Screening for Drug Combinations

  • Paul Shinn
  • Lu Chen
  • Marc Ferrer
  • Zina Itkin
  • Carleen Klumpp-Thomas
  • Crystal McKnight
  • Sam Michael
  • Tim Mierzwa
  • Craig Thomas
  • Kelli Wilson
  • Rajarshi GuhaEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1939)

Abstract

The identification of drug combinations as alternatives to single-agent therapeutics has traditionally been a slow, largely manual process. In the last 10 years, high-throughput screening platforms have been developed that enable routine screening of thousands of drug pairs in an in vitro setting. In this chapter, we describe the workflow involved in screening a single agent versus a library of mechanistically annotated, investigation, and approved drugs using a full dose-response matrix scheme using viability as the readout. We provide details of the automation required to run the screen and the informatics required to process data from screening robot and subsequent analysis and visualization of the datasets.

Key words

Drug combination screening Acoustic dispensing Automation Compound management Synergy 

Notes

Acknowledgments

We would like to thank Lesley Mathews-Griner, John Keller, and Don Liu for their contributions to the development of the NCATS combination screening platform.

References

  1. 1.
    Borisy AA et al (2003) Systematic discovery of multicomponent therapeutics. Proc. Nat. Acad. Sci 100:7977–7982CrossRefGoogle Scholar
  2. 2.
    Lehár J et al (2007) Chemical combination effects predict connectivity in biological systems. Mol Sys Bio 3:80Google Scholar
  3. 3.
    Lehár J et al (2009) Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nat. Biotech. 27:659–666CrossRefGoogle Scholar
  4. 4.
    Bansal M et al (2014) A community computational challenge to predict the activity of pairs of compounds. Nat. Biotech. 32:1213–1222CrossRefGoogle Scholar
  5. 5.
    Attene-Ramos M et al (2013) The Tox21 robotic platform for the assessment of environmental chemicals—from vision to reality. Drug Discov Today 18:716–723CrossRefGoogle Scholar
  6. 6.
    Yasgar A, Shinn P, Jadhav A et al (2008) Compound management for quantitative high-throughput screening. JALA 13:79–89PubMedGoogle Scholar
  7. 7.
    Hafner M et al (2016) Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs. Nat Meth 13:521–527CrossRefGoogle Scholar
  8. 8.
    Heske CM et al (2017) Matrix screen identifies synergistic combination of PARP inhibitors and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors in Ewing sarcoma. Clin Cancer Res 23(23):7301–7311CrossRefGoogle Scholar
  9. 9.
    Malo N, Hanley J, Cerquozzi S, Pelletier J, Nadon R (2006) Statistical practice in high-throughput screening data analysis. Nat Biotech 24:167–175CrossRefGoogle Scholar
  10. 10.
    Zhang XD (2007) A pair of new statistical parameters for quality control in RNA interference high-throughput screening assays. Genomics 89:552–561CrossRefGoogle Scholar
  11. 11.
    Chen L et al (2016) mQC: a heuristic quality-control metric for high-throughput drug combination screening. Sci Rep 6:37741CrossRefGoogle Scholar
  12. 12.
    Borisy AA et al (2003) Systematic discovery of multicomponent therapeutics. Proc. Natl. Acad. Sci 100:7977–7982CrossRefGoogle Scholar
  13. 13.
    Schindler M (2017) Theory of synergistic effects: hill-type response surfaces as ‘null-interaction’ models for mixtures. Theor Biol Med Model 14:15CrossRefGoogle Scholar
  14. 14.
    Cokol M et al (2011) Systematic exploration of synergistic drug pairs. Mol Syst Biol 7:544CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Paul Shinn
    • 1
  • Lu Chen
    • 1
  • Marc Ferrer
    • 1
  • Zina Itkin
    • 1
  • Carleen Klumpp-Thomas
    • 1
  • Crystal McKnight
    • 1
  • Sam Michael
    • 1
  • Tim Mierzwa
    • 1
  • Craig Thomas
    • 1
  • Kelli Wilson
    • 1
  • Rajarshi Guha
    • 2
    Email author
  1. 1.National Center for Advancing Translational ScienceRockvilleUSA
  2. 2.Vertex PharmaceuticalsRockvilleUSA

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