3CE3

Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor C-MET in complex with a Pyrrolopyridinepyridone based inhibitor

3CE3 の概要

• エントリーDOI: 10.2210/pdb3ce3/pdb
• 関連するPDBエントリー: 3C1X
• 分子名称: Hepatocyte growth factor receptor, 1-(4-fluorophenyl)-N-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide (3 entities in total)
• 機能のキーワード: receptor tyrosine kinase, signal transduction, grb2, shc, atp-binding, glycoprotein, membrane, nucleotide-binding, phosphoprotein, proto-oncogene, transferase, transmembrane, tyrosine-protein kinase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P08581
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35893.45

構造登録者

Sack, J. (登録日: 2008-02-28, 公開日: 2008-08-26, 最終更新日: 2024-02-21)

主引用文献

Kim, K.S.,Zhang, L.,Schmidt, R.,Cai, Z.W.,Wei, D.,Williams, D.K.,Lombardo, L.J.,Trainor, G.L.,Xie, D.,Zhang, Y.,An, Y.,Sack, J.S.,Tokarski, J.S.,Darienzo, C.,Kamath, A.,Marathe, P.,Zhang, Y.,Lippy, J.,Jeyaseelan, R.,Wautlet, B.,Henley, B.,Gullo-Brown, J.,Manne, V.,Hunt, J.T.,Fargnoli, J.,Borzilleri, R.M.
Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities.
J.Med.Chem., 51:5330-5341, 2008

PubMed Abstract: Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC50 values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model.

PubMed: 18690676
DOI: 10.1021/jm800476q

実験手法

X-RAY DIFFRACTION (2.4 Å)