Single molecule tracking based drug screening.

ErbB Receptors / metabolism Humans Phosphorylation / drug effects Protein Kinase Inhibitors / pharmacology Single Molecule Imaging / methods Drug Evaluation, Preclinical / methods Epidermal Growth Factor / metabolism Cell Line, Tumor Signal Transduction / drug effects Drug Discovery / methods Cell Proliferation / drug effects

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
17 Oct 2024
Historique:
received: 29 12 2023
accepted: 08 10 2024
medline: 18 10 2024
pubmed: 18 10 2024
entrez: 17 10 2024
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-53432-w PMID: 39420015
pubmed: 39420015
doi: 10.1038/s41467-024-53432-w
pii: 10.1038/s41467-024-53432-w
doi:

Substances chimiques

ErbB Receptors EC 2.7.10.1
Protein Kinase Inhibitors 0
EGFR protein, human EC 2.7.10.1
Epidermal Growth Factor 62229-50-9

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

8975

Subventions

Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP23ym0126815
Organisme : MEXT | JST | Core Research for Evolutional Science and Technology (CREST)
ID : JPMJCR21E1
Organisme : Ministry of Education, Culture, Sports, Science and Technology (MEXT)
ID : 18H01839
Organisme : Ministry of Education, Culture, Sports, Science and Technology (MEXT)
ID : 22H02593
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 18H05414

Informations de copyright

© 2024. The Author(s).

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Auteurs

Daisuke Watanabe (D)

Laboratory of Single Molecule Biology, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
Laboratory for Cell Signaling Dynamics, Center for Biosystems Dynamics Research, RIKEN, Suita, Osaka, Japan.
ORCID: 0009-0007-3330-6582

Michio Hiroshima (M)

Laboratory of Single Molecule Biology, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan. m_hiroshima.fbs@osaka-u.ac.jp.
Laboratory for Cell Signaling Dynamics, Center for Biosystems Dynamics Research, RIKEN, Suita, Osaka, Japan. m_hiroshima.fbs@osaka-u.ac.jp.
ORCID: 0009-0000-0613-6724

Masato Yasui (M)

ZIDO Corporation, Toyonaka, Osaka, Japan.
ORCID: 0009-0000-9481-8732

Masahiro Ueda (M)

Laboratory of Single Molecule Biology, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan. ueda.masahiro.fbs@osaka-u.ac.jp.
Laboratory for Cell Signaling Dynamics, Center for Biosystems Dynamics Research, RIKEN, Suita, Osaka, Japan. ueda.masahiro.fbs@osaka-u.ac.jp.
Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan. ueda.masahiro.fbs@osaka-u.ac.jp.
ORCID: 0000-0002-9354-3404

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteur facteur croissance › Récepteurs ErbB › Single molecule tracking based drug screening.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Single molecule tracking based drug screening.
questionsmedicales.fr › Métabolisme › Phosphorylation › Single molecule tracking based drug screening.
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › Single molecule tracking based drug screening.
questionsmedicales.fr › Techniques d'investigation › Techniques de sonde moléculaire › Imagerie moléculaire › Imagerie de molécules uniques › Single molecule tracking based drug screening.
questionsmedicales.fr › Techniques d'investigation › Évaluation préclinique de médicament › Single molecule tracking based drug screening.
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines de la famille de l'EGF › Facteur de croissance épidermique › Single molecule tracking based drug screening.
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Single molecule tracking based drug screening.
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Single molecule tracking based drug screening.
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Single molecule tracking based drug screening.
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Single molecule tracking based drug screening.