Title of article :
Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase
Author/Authors :
Gretchen M. Schroeder، نويسنده , , Xiao-Tao Chen، نويسنده , , David K. Williams، نويسنده , , David S. Nirschl، نويسنده , , Zhen-wei Cai، نويسنده , , Donna Wei، نويسنده , , John S. Tokarski، نويسنده , , Yongmi An، نويسنده , , John Sack، نويسنده , , Zhong Chen، نويسنده , , Tram Huynh، نويسنده , , Wayne Vaccaro، نويسنده , , Michael Poss، نويسنده , , Barri Wautlet، نويسنده , , Johnni Gullo-Brown، نويسنده , , Kristen Kellar، نويسنده , , Veeraswamy Manne، نويسنده , , John T. Hunt، نويسنده , , Tai W. Wong، نويسنده , , Louis J. Lombardo، نويسنده , , et al.، نويسنده ,
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.
Keywords :
Hepatocyte growth factor receptor , Met kinase , HGFR , Gastric carcinoma , Pyrrolotriazine
