title: Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase.
abstract: Tumorigenesis is a multistep process in which oncogenes play a key role in tumor formation, growth, and maintenance. MET was discovered as an oncogene that is activated by its ligand, hepatocyte growth factor. Deregulated signaling in the c-Met pathway has been observed in multiple tumor types. Herein we report the discovery of potent and selective triazolopyridazine small molecules that inhibit c-Met activity.
authors.affiliation: Amgen Inc., Cambridge, MA 02139, USA. brian.albrecht@amgen.com
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
authors.forename: David
authors.initials: D
authors.lastname: Bauer
authors.forename: Loren
authors.initials: L
authors.lastname: Berry
authors.forename: Christiane
authors.initials: C
authors.lastname: Bode
authors.forename: Alessandro A
authors.initials: AA
authors.lastname: Boezio
authors.forename: April
authors.initials: A
authors.lastname: Chen
authors.forename: Deborah
authors.initials: D
authors.lastname: Choquette
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dussault
authors.forename: Cary
authors.initials: C
authors.lastname: Fridrich
authors.forename: Satoko
authors.initials: S
authors.lastname: Hirai
authors.forename: Doug
authors.initials: D
authors.lastname: Hoffman
authors.forename: Jay F
authors.initials: JF
authors.lastname: Larrow
authors.forename: Paula
authors.initials: P
authors.lastname: Kaplan-Lefko
authors.forename: Jasmine
authors.initials: J
authors.lastname: Lin
authors.forename: Julia
authors.initials: J
authors.lastname: Lohman
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Long
authors.forename: Jodi
authors.initials: J
authors.lastname: Moriguchi
authors.forename: Anne
authors.initials: A
authors.lastname: O'Connor
authors.forename: Michele H
authors.initials: MH
authors.lastname: Potashman
authors.forename: Monica
authors.initials: M
authors.lastname: Reese
authors.forename: Karen
authors.initials: K
authors.lastname: Rex
authors.forename: Aaron
authors.initials: A
authors.lastname: Siegmund
authors.forename: Kavita
authors.initials: K
authors.lastname: Shah
authors.forename: Roman
authors.initials: R
authors.lastname: Shimanovich
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Springer
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Teffera
authors.forename: Yajing
authors.initials: Y
authors.lastname: Yang
authors.forename: Yihong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Steven F
authors.initials: SF
authors.lastname: Bellon
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D017228:Hepatocyte Growth Factor / Q000502:physiology; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D011724:Pyridazines; D014230:Triazoles; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met