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Single molecule tracking based drug screening

Author

Listed:
  • Daisuke Watanabe

    (Osaka University
    RIKEN)

  • Michio Hiroshima

    (Osaka University
    RIKEN)

  • Masato Yasui

    (ZIDO Corporation)

  • Masahiro Ueda

    (Osaka University
    RIKEN
    Osaka University)

Abstract

The single-molecule tracking of transmembrane receptors in living cells has provided significant insights into signaling mechanisms, such as mobility and clustering upon their activation/inactivation, making it a potential screening method for drug discovery. Here we show that single-molecule tracking-based screening can be used to explore compounds both detectable and undetectable by conventional methods for disease-related receptors. Using an automated system for a fast large-scale single-molecule analysis, we screen for epidermal growth factor receptor (EGFR) from 1134 of FDA approved drugs. The 18 hit compounds include all EGFR-targeted tyrosine kinase inhibitors (TKIs) in the library that suppress any phosphorylation-dependent mobility shift of EGFR, proving the concept of this approach. The remaining hit compounds are not reported as EGFR-targeted drugs and do not inhibit EGF-induced EGFR phosphorylation. These non-TKI compounds affect the mobility and/or clustering of EGFR without EGF and induce EGFR internalization, to impede EGFR-dependent cell growth. Thus, single-molecule tracking provides an alternative modality for discovering therapeutics on various receptor functions with previously untargeted mechanisms.

Suggested Citation

  • Daisuke Watanabe & Michio Hiroshima & Masato Yasui & Masahiro Ueda, 2024. "Single molecule tracking based drug screening," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53432-w
    DOI: 10.1038/s41467-024-53432-w
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    References listed on IDEAS

    as
    1. Masato Yasui & Michio Hiroshima & Jun Kozuka & Yasushi Sako & Masahiro Ueda, 2018. "Automated single-molecule imaging in living cells," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    2. E. Bourseau-Guilmain & J. A. Menard & E. Lindqvist & V. Indira Chandran & H. C. Christianson & M. Cerezo Magaña & J. Lidfeldt & G. Marko-Varga & C. Welinder & M. Belting, 2016. "Hypoxia regulates global membrane protein endocytosis through caveolin-1 in cancer cells," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
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