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Protein–Protein Interaction Inhibitors of BRCA1 Discovered Using Small Molecule Microarrays

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Small Molecule Microarrays

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1518))

Abstract

Microarray screening technology has transformed the life sciences arena over the last decade. The platform is widely used in the area of mapping interaction networks, to molecular fingerprinting and small molecular inhibitor discovery. The technique has significantly impacted both basic and applied research. The microarray platform can likewise enable high-throughput screening and discovery of protein–protein interaction (PPI) inhibitors. Herein we demonstrate the application of microarray-guided PPI inhibitor discovery, using human BRCA1 as an example. Mutations in BRCA1 have been implicated in ~50 % of hereditary breast cancers. By targeting the (BRCT)2 domain, we showed compound 15a and its prodrug 15b inhibited BRCA1 activities in tumor cells. Unlike previously reported peptide-based PPI inhibitors of BRCA1, the compounds identified could be directly administered to tumor cells, thus making them useful in targeting BRCA1/PARP-related pathways involved in DNA damage and repair response, for cancer therapy.

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Acknowledgment

Funding was provided by the Singapore National Medical Research Council (CBRG12nov100) and the Ministry of Education (MOE2012-T2-1-116, MOE2012-T2-2-051, and MOE2013-T2-1-048). We also acknowledge the financial support from the Singapore-Peking-Oxford Research Enterprise (COY-15-EWI-RCFSA/N197-1).

Author information

Authors and Affiliations

  1. Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore, 117543, Singapore

    Zhenkun Na, Sijun Pan & Mahesh Uttamchandani

  2. Defence Medical & Environmental Research Institute, DSO National Laboratories, Singapore, Singapore

    Mahesh Uttamchandani

  3. Department of Chemistry, Faculty of Science, National University of Singapore, 3 Science Drive 3, Singapore, 117543, Singapore

    Shao Q. Yao

Authors
  1. Zhenkun Na
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  2. Sijun Pan
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  3. Mahesh Uttamchandani
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  4. Shao Q. Yao
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Corresponding author

Correspondence to Shao Q. Yao .

Editor information

Editors and Affiliations

  1. DSO National Laboratories, Defence Medical and Environmental Resear, Singapore, Singapore

    Mahesh Uttamchandani

  2. Department of Chemistry Faculty of Science, National University of Singapore, Singapore, Singapore

    Shao Q. Yao

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Na, Z., Pan, S., Uttamchandani, M., Yao, S.Q. (2017). Protein–Protein Interaction Inhibitors of BRCA1 Discovered Using Small Molecule Microarrays. In: Uttamchandani, M., Yao, S. (eds) Small Molecule Microarrays. Methods in Molecular Biology, vol 1518. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6584-7_10

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  • DOI: https://doi.org/10.1007/978-1-4939-6584-7_10

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-6582-3

  • Online ISBN: 978-1-4939-6584-7

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