title: Design, synthesis and structure-activity relationships of novel biarylamine-based Met kinase inhibitors.
abstract: 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.
authors.affiliation: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. david.williams@bms.com
authors.forename: David K
authors.initials: DK
authors.lastname: Williams
authors.forename: Xiao-Tao
authors.initials: XT
authors.lastname: Chen
authors.forename: Christine
authors.initials: C
authors.lastname: Tarby
authors.forename: Robert
authors.initials: R
authors.lastname: Kaltenbach
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Cai
authors.forename: John S
authors.initials: JS
authors.lastname: Tokarski
authors.forename: Yongmi
authors.initials: Y
authors.lastname: An
authors.forename: John S
authors.initials: JS
authors.lastname: Sack
authors.forename: Barri
authors.initials: B
authors.lastname: Wautlet
authors.forename: Johnni
authors.initials: J
authors.lastname: Gullo-Brown
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Henley
authors.forename: Robert
authors.initials: R
authors.lastname: Jeyaseelan
authors.forename: Kristen
authors.initials: K
authors.lastname: Kellar
authors.forename: Veeraswamy
authors.initials: V
authors.lastname: Manne
authors.forename: George L
authors.initials: GL
authors.lastname: Trainor
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
authors.forename: Robert M
authors.initials: RM
authors.lastname: Borzilleri
mesh_terms: 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
chemical_list: D000588:Amines; D000631:Aminopyridines; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met