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A Natural Products Approach to Drug Discovery: Probing Modes of Action of Antitumor Agents by Genome-Scale cDNA Library Screening

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Ligand-Macromolecular Interactions in Drug Discovery

Part of the book series: Methods in Molecular Biology ((MIMB,volume 572))

Summary

In the last few years, genomic tools have been incorporated in natural product approaches to drug discovery, including understanding mechanisms of action which cannot be elucidated from phenotypic screens such as cell viability assays. The characterization of perturbed biological pathways and target identification are important for the evaluation of the compounds’ potential as drug leads and for subsequent medicinal chemistry efforts; however, general procedures to tackle this task are lacking. The combination of high-throughput screening and genomic-scale assays has proven to be a powerful tool to aid in the identification of mechanisms and potentially of protein targets, not only in yeast but also mammalian cells. Arrayed libraries of cDNAs can be transfected into cancer cell lines in a high-throughput fashion to generate variants of spatially separated cancer cells with increased gene dosages for one particular cDNA. Cells overexpressing gene products that are directly targeted by a small molecule or that lie in the perturbed pathway may be less susceptible to the effects of the compound. This fact provides the basis for drug susceptibility screens employing cDNA libraries. The general procedures to optimize and execute those screens and subsequently validate putative screening hits are discussed in detail.

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Acknowledgments

H. L. received a Junior Investigator Award (pilot grant) from the University of Florida Shands Cancer Center, American Cancer Society, Institutional Research Grant, ACS-IRG-01–188–01. Further funding to H. L. to study mechanisms of anticancer drug action is provided by the James & Esther King Biomedical Research Program, Grant No. 06-NIR07.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, University of Florida, Gainesville, FL, USA

    Hendrik Luesch

  2. REQUIMTE, Department of Chemistry, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal

    Pedro Abreu

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  1. Hendrik Luesch
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  2. Pedro Abreu
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Editors and Affiliations

  1. Fac. Ciências e Tecnologia, Depto. Química, Universidade Nova de Lisboa, Quinta da Torre, Caparica, 2829-516, Portugal

    Ana Cecília A. Roque

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© 2010 Humana Press

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Luesch, H., Abreu, P. (2010). A Natural Products Approach to Drug Discovery: Probing Modes of Action of Antitumor Agents by Genome-Scale cDNA Library Screening. In: Roque, A. (eds) Ligand-Macromolecular Interactions in Drug Discovery. Methods in Molecular Biology, vol 572. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-244-5_17

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  • DOI: https://doi.org/10.1007/978-1-60761-244-5_17

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60761-243-8

  • Online ISBN: 978-1-60761-244-5

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