title: Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity.
abstract: Deregulation of the receptor tyrosine kinase mesenchymal epithelial transition factor (MET) has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of compound 23 (AMG 337), which demonstrates nanomolar inhibition of MET kinase activity, desirable preclinical pharmacokinetics, significant inhibition of MET phosphorylation in mice, and robust tumor growth inhibition in a MET-dependent mouse efficacy model.
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Alessandro A
authors.initials: AA
authors.lastname: Boezio
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Katrina W
authors.initials: KW
authors.lastname: Copeland
authors.affiliation: Amgen Incorporated , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Rex
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: K Albrecht
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: David
authors.initials: D
authors.lastname: Bauer
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Bellon
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Christiane
authors.initials: C
authors.lastname: Boezio
authors.affiliation: Amgen Incorporated , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Broome
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Deborah
authors.initials: D
authors.lastname: Choquette
authors.affiliation: Amgen Incorporated , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
authors.affiliation: Amgen Incorporated , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dussault
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Satoko
authors.initials: S
authors.lastname: Hirai
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Lewis
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Min-Hwa Jasmine
authors.initials: MH
authors.lastname: Lin
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Julia
authors.initials: J
authors.lastname: Lohman
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Jingzhou
authors.initials: J
authors.lastname: Liu
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Peterson
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Michele
authors.initials: M
authors.lastname: Potashman
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Roman
authors.initials: R
authors.lastname: Shimanovich
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Teffera
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Karina R
authors.initials: KR
authors.lastname: Vaida
authors.affiliation: Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000609912:AMG 337; D000970:Antineoplastic Agents; D011728:Pyridones; D014230:Triazoles; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met