High Content Screening as a Screening Tool in Drug Discovery

  • Anthony Nichols
Part of the Methods in Molecular Biology book series (MIMB, volume 356)


In most pharmaceutical and biotechnology companies there is a need to always improve the quality of lead candidates. This demand resulted in the use of cell-based screening as a method of choice in drug discovery (1,2). High content screening (HCS) is multiplexed, functional cell-based screening (3, 4, 5, 6). HCS can be used in all aspects of drug discovery as an engine for driving lead discovery. The biological applications of HCS have been implemented in research in signaling, cell shape changes and toxicology. HCS has enabled an insight in the cellular effects of our clinical candidates in multiple cellular phenomena like dual reporter assay, subcellular target translocation and cellular morphology. Discovery of therapeutic protein and small molecule converge on diseases in therapeutic areas such neurological disorders and autoimmune diseases. HCS is used for assay development, primary, secondary screening and toxicology testing. In this chapter, the use of HCS assays in drug discovery is described and highlight the necessary step to set-up successfully these assays for screening.

Key Words

Cell-based assays cell-membrane translocation cell morphology assays dual reporter assays genotoxicity high content screening (HCS) micronucleus nuclear translocation 


  1. 1.
    Gribbon, P. and Sewing, A. (2003) Fluorescence readouts in HTS: no gain without pain? Drug Discov. Today 8, 1035–1043.CrossRefGoogle Scholar
  2. 2.
    Johnston, P. A. and Johnston, P. A. (2002) Cellular platforms for HTS: three case studies. Drug Discov. Today 7, 353–363.CrossRefGoogle Scholar
  3. 3.
    Abraham, V. C., Taylor, D. L., and Haskins, J. R. (2004) High content screening applied to large scale cell biology. Trends Biotechnol. 22, 15–22.CrossRefGoogle Scholar
  4. 4.
    Alessi, D. R. and Downes, C. P. (1998). The role of PI 3-kinase in insulin action. Biochim. Biophys. Acta 1436, 151–164.Google Scholar
  5. 5.
    Giuliano, K. A., Haskins, J. R., and Taylor, D. L. (2003) Advances in high content screening for drug discovery. Assay. Drug Dev. Technol. 1, 565–577.CrossRefGoogle Scholar
  6. 6.
    Johnston, P. (2002) Cellular assays in HTS. Methods Mol. Biol. 190, 107–116.Google Scholar
  7. 7.
    Russello, S. V. (2004) Assessing cellular protein phosphorylation: high throughput drug discovery technologies. Assay. Drug Dev. Technol. 2, 225–235.CrossRefGoogle Scholar
  8. 8.
    Taylor, D. L., Woo, E. S., and Giuliano, K. A. (2001). Real-time molecular and cellular analysis: the new frontier of drug discovery. Curr. Opin. Biotechnol. 12, 75–81.CrossRefGoogle Scholar
  9. 9.
    Vogt, A., Cooley, K. A., Brisson, M., Tarpley, M. G., Wipf, P., and Lazo, J. S. (2003) Cell-active dual specificity phosphatase inhibitors identified by high content screening. Chem. Biol. 10, 733–742.CrossRefGoogle Scholar
  10. 10.
    Ramm, P. and Thomas, N. (2003) Image-based screening of signal transduction assays. Sci. STKE. 2003, E14.CrossRefGoogle Scholar
  11. 11.
    Gaillard, P., Jeanclaude-Etter, I., Ardissone, V., et al. (2005) Design and synthesis of the first generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-jun N-terminal kinase. J. Med. Chem. 48, 4596–4607.CrossRefGoogle Scholar
  12. 12.
    Manning, A. M. and Davis, R. J. (2003) Targeting JNK for therapeutic benefit: from junk to gold? Nat. Rev. Drug Discov. 2, 554–565.CrossRefGoogle Scholar
  13. 13.
    Ruckle, T., Biamonte, M., Grippi-Vallotton, T., et al. (2004) Design, synthesis, and biological activity of novel, potent, and selective (benzoylaminomethyl)thiophene sulfonamide inhibitors of c-Jun-N-terminal kinase. J. Med. Chem. 47, 6921–6934.CrossRefGoogle Scholar
  14. 14.
    Lin, A., Minden, A., Martinetto, H., et al. (1995). Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science 268, 286–290.CrossRefGoogle Scholar
  15. 15.
    Ding, G. J., Fischer, P. A., Boltz, R. C., et al. (1998) Characterization and quantitation of NF-kappaB nuclear translocation induced by interleukin-1 and tumor necrosis factor-alpha. Development and use of a high capacity fluorescence cytometric system. J. Biol. Chem. 273, 28,897–28,905.CrossRefGoogle Scholar
  16. 16.
    Vakkila, J., DeMarco, R. A., and Lotze, M. T. (2004) Imaging analysis of STAT1 and NF-kappaB translocation in dendritic cells at the single cell level. J. Immunol. Methods 294, 123–134.CrossRefGoogle Scholar
  17. 17.
    Karin, M., Yamamoto, Y., and Wang, Q. M. (2004) The IKK NF-kappa B system: a treasure trove for drug development. Nat. Rev. Drug Discov. 3, 17–26.CrossRefGoogle Scholar
  18. 18.
    Mielke, K., Damm, A., Yang, D. D., and Herdegen, T. (2000) Selective expression of JNK isoforms and stress-specific JNK activity in different neural cell lines. Brain Res. Mol. Brain Res. 75, 128–137.CrossRefGoogle Scholar
  19. 19.
    Buckman, T. D., Sutphin, M. S., and Mitrovic, B. (1993) Oxidative stress in a clonal cell line of neuronal origin: effects of antioxidant enzyme modulation. J. Neurochem. 60, 2046–2058.CrossRefGoogle Scholar
  20. 20.
    Hurley, J. H. and Meyer, T. (2001). Subcellular targeting by membrane lipids. Curr. Opin. Cell Biol. 13, 146–152.CrossRefGoogle Scholar
  21. 21.
    Lundholt, B. K., Linde, V., Loechel, F., et al. (2005) Identification of Akt pathway inhibitors using redistribution screening on the FLIPR and the IN Cell 3000 analyzer. J. Biomol. Screen. 10, 20–29.CrossRefGoogle Scholar
  22. 22.
    Fields, R. D. and Nelson, P. G. (1992) Activity-dependent development of the vertebrate nervous system. Int. Rev. Neurobiol. 34, 133–214.CrossRefGoogle Scholar
  23. 23.
    Thoenen, H. (1991) The changing scene of neurotrophic factors. Trends Neurosci. 14, 165–170.CrossRefGoogle Scholar
  24. 24.
    Ramm, P., Alexandrov, Y., Cholewinski, A., Cybuch, Y., Nadon, R., and Soltys, B. J. (2003) Automated screening of neurite outgrowth. J. Biomol. Screen. 8, 7–18.CrossRefGoogle Scholar
  25. 25.
    Kirsch-Volders, M., Sofuni, T., Aardema, M., et al. (2003) Report from the in vitro micronucleus assay working group. Mutat. Res. 540, 153–163.Google Scholar

Copyright information

© Humana Press, Inc. 2007

Authors and Affiliations

  • Anthony Nichols
    • 1
  1. 1.Molecular Screening and Cell Pharmacology DepartmentSerono Pharmaceutical Research InstituteGenevaSwitzerland

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