A drug discovery platform to identify compounds that inhibit EGFR triple mutants.
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Cell Line
Cell Line, Tumor
DNA Nucleotidyltransferases
/ genetics
Drug Discovery
Drug Resistance, Neoplasm
/ genetics
ErbB Receptors
/ antagonists & inhibitors
Genes, Reporter
High-Throughput Screening Assays
/ methods
Humans
Luciferases
/ genetics
Lung Neoplasms
/ drug therapy
Mutation
Phosphorylation
/ drug effects
Protein Kinase Inhibitors
/ pharmacology
Reproducibility of Results
Small Molecule Libraries
/ pharmacology
Staurosporine
/ analogs & derivatives
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
18
10
2017
accepted:
27
01
2020
pubmed:
26
2
2020
medline:
21
7
2020
entrez:
26
2
2020
Statut:
ppublish
Résumé
Receptor tyrosine kinases (RTKs) are transmembrane receptors of great clinical interest due to their role in disease. Historically, therapeutics targeting RTKs have been identified using in vitro kinase assays. Due to frequent development of drug resistance, however, there is a need to identify more diverse compounds that inhibit mutated but not wild-type RTKs. Here, we describe MaMTH-DS (mammalian membrane two-hybrid drug screening), a live-cell platform for high-throughput identification of small molecules targeting functional protein-protein interactions of RTKs. We applied MaMTH-DS to an oncogenic epidermal growth factor receptor (EGFR) mutant resistant to the latest generation of clinically approved tyrosine kinase inhibitors (TKIs). We identified four mutant-specific compounds, including two that would not have been detected by conventional in vitro kinase assays. One of these targets mutant EGFR via a new mechanism of action, distinct from classical TKI inhibition. Our results demonstrate how MaMTH-DS is a powerful complement to traditional drug screening approaches.
Identifiants
pubmed: 32094923
doi: 10.1038/s41589-020-0484-2
pii: 10.1038/s41589-020-0484-2
pmc: PMC8123931
mid: NIHMS1698228
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Small Molecule Libraries
0
Luciferases
EC 1.13.12.-
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
DNA Nucleotidyltransferases
EC 2.7.7.-
FLP recombinase
EC 2.7.7.-
Staurosporine
H88EPA0A3N
midostaurin
ID912S5VON
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
577-586Subventions
Organisme : NCI NIH HHS
ID : R01 CA079992
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA198164
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM122485
Pays : United States
Commentaires et corrections
Type : CommentIn
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