3c1x

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Template:STRUCTURE 3c1x

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

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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.

Disease

Known disease associated with this structure: Hepatocellular carcinoma, childhood type OMIM:[164860], Renal cell carcinoma, papillary, familial and sporadic OMIM:[164860], Autism, suseptibility to, 9 OMIM:[164860]

About this Structure

3C1X is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase., Schroeder GM, Chen XT, Williams DK, Nirschl DS, Cai ZW, Wei D, Tokarski JS, An Y, Sack J, Chen Z, Huynh T, Vaccaro W, Poss M, Wautlet B, Gullo-Brown J, Kellar K, Manne V, Hunt JT, Wong TW, Lombardo LJ, Fargnoli J, Borzilleri RM, Bioorg Med Chem Lett. 2008 Mar 15;18(6):1945-51. Epub 2008 Feb 7. PMID:18289854 Page seeded by OCA on Sun May 4 21:17:44 2008