3C1X

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

3C1X の概要

• エントリーDOI: 10.2210/pdb3c1x/pdb
• 分子名称: Hepatocyte growth factor receptor, N-{[4-({5-[(4-aminopiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl}oxy)-3-fluorophenyl]carbamoyl}-2-(4-fluorophenyl)acetamide (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: 42384.82

構造登録者

Sack, J. (登録日: 2008-01-24, 公開日: 2008-03-18, 最終更新日: 2024-02-21)

主引用文献

Schroeder, G.M.,Chen, X.T.,Williams, D.K.,Nirschl, D.S.,Cai, Z.W.,Wei, D.,Tokarski, J.S.,An, Y.,Sack, J.,Chen, Z.,Huynh, T.,Vaccaro, W.,Poss, M.,Wautlet, B.,Gullo-Brown, J.,Kellar, K.,Manne, V.,Hunt, J.T.,Wong, T.W.,Lombardo, L.J.,Fargnoli, J.,Borzilleri, R.M.
Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase.
Bioorg.Med.Chem.Lett., 18:1945-1951, 2008

PubMed Abstract: An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner.

PubMed: 18289854
DOI: 10.1016/j.bmcl.2008.01.121

実験手法

X-RAY DIFFRACTION (2.17 Å)