Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase.
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.
Schroeder
Gretchen M
GM
Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. gretchen.schroeder@bms.com
Chen
Xiao-Tao
XT
Williams
David K
DK
Nirschl
David S
DS
Cai
Zhen-Wei
ZW
Wei
Donna
D
Tokarski
John S
JS
An
Yongmi
Y
Sack
John
J
Chen
Zhong
Z
Huynh
Tram
T
Vaccaro
Wayne
W
Poss
Michael
M
Wautlet
Barri
B
Gullo-Brown
Johnni
J
Kellar
Kristen
K
Manne
Veeraswamy
V
Hunt
John T
JT
Wong
Tai W
TW
Lombardo
Louis J
LJ
Fargnoli
Joseph
J
Borzilleri
Robert M
RM
D000818:Animals; D018938:Caco-2 Cells / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D011758:Pyrroles / Q000737:chemistry*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry*
D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D017978:Receptors, Growth Factor; D014227:Triazines; D005982:Glutathione Transferase; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases