TAS0728, A Covalent-binding, HER2-selective Kinase Inhibitor Shows Potent Antitumor Activity in Preclinical Models.
Animals
Antineoplastic Agents
/ administration & dosage
Apoptosis
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Drug Evaluation, Preclinical
/ methods
Humans
Mass Spectrometry
Mice
Mice, Inbred BALB C
Mice, Nude
Mice, SCID
Phosphorylation
/ drug effects
Protein Binding
Protein Kinase Inhibitors
/ administration & dosage
Receptor, ErbB-2
/ antagonists & inhibitors
Receptor, ErbB-3
/ antagonists & inhibitors
Recombinant Proteins
Signal Transduction
/ drug effects
Tumor Burden
/ drug effects
Xenograft Model Antitumor Assays
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
21
09
2018
revised:
09
12
2018
accepted:
22
01
2019
pubmed:
23
2
2019
medline:
27
2
2020
entrez:
22
2
2019
Statut:
ppublish
Résumé
Activated HER2 is a promising therapeutic target for various cancers. Although several reports have described HER2 inhibitors in development, no covalent-binding inhibitor selective for HER2 has been reported. Here, we report a novel compound TAS0728 that covalently binds to HER2 at C805 and selectively inhibits its kinase activity. Once TAS0728 bound to HER2 kinase, the inhibitory activity was not affected by a high ATP concentration. A kinome-wide biochemical panel and cellular assays established that TAS0728 possesses high specificity for HER2 over wild-type EGFR. Cellular pharmacodynamics assays using MCF10A cells engineered to express various mutated
Identifiants
pubmed: 30787176
pii: 1535-7163.MCT-18-1085
doi: 10.1158/1535-7163.MCT-18-1085
doi:
Substances chimiques
Antineoplastic Agents
0
Protein Kinase Inhibitors
0
Recombinant Proteins
0
ERBB2 protein, human
EC 2.7.10.1
ERBB3 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Receptor, ErbB-3
EC 2.7.10.1
Banques de données
ClinicalTrials.gov
['NCT03410927']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
733-742Informations de copyright
©2019 American Association for Cancer Research.