4R1Y

Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitor

4R1Y の概要

• エントリーDOI: 10.2210/pdb4r1y/pdb
• 関連するPDBエントリー: 4R1V
• 分子名称: Hepatocyte growth factor receptor, 3-(diethylamino)propyl (3-{[5-(3,4-dimethoxyphenyl)-2-oxo-2H-1,3,4-thiadiazin-3(6H)-yl]methyl}phenyl)carbamate, 2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL, ... (4 entities in total)
• 機能のキーワード: transferase inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein. Isoform 3: Secreted: P08581
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34183.83

構造登録者

Blaukat, A.,Bladt, F.,Friese-Hamim, M.,Knuehl, C.,Fittschen, C.,Graedler, U.,Meyring, M.,Dorsch, D.,Stieber, F.,Schadt, O. (登録日: 2014-08-08, 公開日: 2015-03-18, 最終更新日: 2024-02-28)

主引用文献

Dorsch, D.,Schadt, O.,Stieber, F.,Meyring, M.,Gradler, U.,Bladt, F.,Friese-Hamim, M.,Knuhl, C.,Pehl, U.,Blaukat, A.
Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors.
Bioorg.Med.Chem.Lett., 25:1597-1602, 2015

PubMed Abstract: In a high-throughput screening campaign for c-Met kinase inhibitors, a thiadiazinone derivative with a carbamate group was identified as a potent in vitro inhibitor. Subsequent optimization guided by c-Met-inhibitor X-ray structures furnished new compound classes with excellent in vitro and in vivo profiles. The thiadiazinone ring of the HTS hit was first replaced by a pyridazinone followed by an exchange of the carbamate hinge binder with a 1,5-disubstituted pyrimidine. Finally an optimized compound, 22 (MSC2156119), with excellent in vitro potency, high kinase selectivity, long half-life after oral administration and in vivo anti-tumor efficacy at low doses, was selected as a candidate for clinical development.

PubMed: 25736998
DOI: 10.1016/j.bmcl.2015.02.002

実験手法

X-RAY DIFFRACTION (2 Å)