Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase.

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.

• Authors: Gretchen M Schroeder, Xiao-Tao Chen, David K Williams, David S Nirschl, Zhen-Wei Cai, Donna Wei, John S Tokarski, Yongmi An, John Sack, Zhong Chen, Tram Huynh, Wayne Vaccaro, Michael Poss, Barri Wautlet, Johnni Gullo-Brown, Kristen Kellar, Veeraswamy Manne, John T Hunt, Tai W Wong, Louis J Lombardo, Joseph Fargnoli, Robert M Borzilleri
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 18 Issue 6 Pg. 1945-51 (Mar 15 2008) ISSN: 1464-3405 [Electronic] England
• PMID: 18289854 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Ether-A-Go-Go Potassium Channels
• KCNH1 protein, human
• Proto-Oncogene Proteins
• Pyrroles
• Receptors, Growth Factor
• Triazines
• Glutathione Transferase
• MET protein, human
• Proto-Oncogene Proteins c-met
• RON protein
• Receptor Protein-Tyrosine Kinases

Topics

• Animals
• Caco-2 Cells (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured (drug effects)
• Crystallography, X-Ray
• Enzyme Inhibitors (chemical synthesis, pharmacokinetics, pharmacology)
• Ether-A-Go-Go Potassium Channels (antagonists & inhibitors)
• Glutathione Transferase (antagonists & inhibitors)
• Hepatocytes (drug effects, metabolism)
• Humans
• Mice
• Microsomes, Liver (drug effects, metabolism)
• Molecular Structure
• Protein Conformation
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-met
• Pyrroles (chemistry)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Receptors, Growth Factor (antagonists & inhibitors, metabolism)
• Stomach Neoplasms (blood, drug therapy, enzymology)
• Structure-Activity Relationship
• Triazines (chemistry)