Design, synthesis and structure-activity relationships of novel biarylamine-based Met kinase inhibitors.
Biarylamine-based inhibitors of Met kinase have been identified. Lead compounds demonstrate nanomolar potency in Met kinase biochemical assays and significant activity in the Met-driven GTL-16 human gastric carcinoma cell line. X-ray crystallography revealed that these compounds adopt a bioactive conformation, in the kinase domain, consistent with that previously seen with 2-pyridone-based Met kinase inhibitors. Compound 9b demonstrated potent in vivo antitumor activity in the GTL-16 human tumor xenograft model.
Williams
David K
DK
Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. david.williams@bms.com
Chen
Xiao-Tao
XT
Tarby
Christine
C
Kaltenbach
Robert
R
Cai
Zhen-Wei
ZW
Tokarski
John S
JS
An
Yongmi
Y
Sack
John S
JS
Wautlet
Barri
B
Gullo-Brown
Johnni
J
Henley
Benjamin J
BJ
Jeyaseelan
Robert
R
Kellar
Kristen
K
Manne
Veeraswamy
V
Trainor
George L
GL
Lombardo
Louis J
LJ
Fargnoli
Joseph
J
Borzilleri
Robert M
RM
D000588:Amines / Q000737:chemistry*; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000588:Amines; D000631:Aminopyridines; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met