3C1X

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

Summary for 3C1X

• Entry DOI: 10.2210/pdb3c1x/pdb
• Descriptor: 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)
• Functional Keywords: receptor tyrosine kinase, signal transduction, grb2, shc, atp-binding, glycoprotein, membrane, nucleotide-binding, phosphoprotein, proto-oncogene, transferase, transmembrane, tyrosine-protein kinase
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P08581
• Total number of polymer chains: 1
• Total formula weight: 42384.82

Authors

Sack, J. (deposition date: 2008-01-24, release date: 2008-03-18, Last modification date: 2024-02-21)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.17 Å)