RRC ID 51842
著者 Novotny CJ, Pollari S, Park JH, Lemmon MA, Shen W, Shokat KM.
タイトル Overcoming resistance to HER2 inhibitors through state-specific kinase binding.
ジャーナル Nat Chem Biol
Abstract The heterodimeric receptor tyrosine kinase complex formed by HER2 and HER3 can act as an oncogenic driver and is also responsible for rescuing a large number of cancers from a diverse set of targeted therapies. Inhibitors of these proteins, particularly HER2, have dramatically improved patient outcomes in the clinic, but recent studies have demonstrated that stimulating the heterodimeric complex, either via growth factors or by increasing the concentrations of HER2 and HER3 at the membrane, significantly diminishes the activity of the inhibitors. To identify an inhibitor of the active HER2-HER3 oncogenic complex, we developed a panel of Ba/F3 cell lines suitable for ultra-high-throughput screening. Medicinal chemistry on the hit scaffold resulted in a previously uncharacterized inhibitor that acts through preferential inhibition of the active state of HER2 and, as a result, is able to overcome cellular mechanisms of resistance such as growth factors or mutations that stabilize the active form of HER2.
巻・号 12(11)
ページ 923-930
公開日 2016-11-1
DOI 10.1038/nchembio.2171
PII nchembio.2171
PMID 27595329
PMC PMC5069157
MeSH Animals Binding Sites / drug effects Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Drug Resistance, Neoplasm / drug effects* Drug Resistance, Neoplasm / genetics High-Throughput Screening Assays Humans Mice Models, Molecular Molecular Structure Protein Kinase Inhibitors / chemistry Protein Kinase Inhibitors / pharmacology* Protein Stability / drug effects Receptor, ErbB-2 / antagonists & inhibitors* Receptor, ErbB-2 / genetics Receptor, ErbB-2 / metabolism
IF 12.587
引用数 15
リソース情報
ヒト・動物細胞 CW-2(RCB0778)