| RRC ID |
81907
|
| Author |
Watanabe D, Hiroshima M, Yasui M, Ueda M.
|
| Title |
Single molecule tracking based drug screening.
|
| Journal |
Nat Commun
|
| 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.
|
| Volume |
15(1)
|
| Pages |
8975
|
| Published |
2024-10-17
|
| DOI |
10.1038/s41467-024-53432-w
|
| PII |
10.1038/s41467-024-53432-w
|
| PMID |
39420015
|
| PMC |
PMC11486946
|
| MeSH |
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Discovery / methods
Drug Evaluation, Preclinical / methods
Epidermal Growth Factor / metabolism
Epidermal Growth Factor / pharmacology
ErbB Receptors* / antagonists & inhibitors
ErbB Receptors* / metabolism
Humans
Phosphorylation / drug effects
Protein Kinase Inhibitors* / pharmacology
Signal Transduction / drug effects
Single Molecule Imaging* / methods
|
| Resource |
| Human and Animal Cells |
CHO-K1(RCB0285)
HeLa((RCB0007)
A431(RCB0202)
Ba/F3(RCB4476) |
