Single molecule tracking based drug screening

Daisuke Watanabe, Michio Hiroshima (), Masato Yasui and Masahiro Ueda ()
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Daisuke Watanabe: Osaka University
Michio Hiroshima: Osaka University
Masato Yasui: ZIDO Corporation
Masahiro Ueda: Osaka University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53432-w

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