title: Discovery of highly potent, selective, and efficacious small molecule inhibitors of ERK1/2.
abstract: Using structure-based design, a novel series of pyridone ERK1/2 inhibitors was developed. Optimization led to the identification of (S)-14k, a potent, selective, and orally bioavailable agent that inhibited tumor growth in mouse xenograft models. On the basis of its in vivo efficacy and preliminary safety profiles, (S)-14k was selected for further preclinical evaluation.
authors.affiliation: Array BioPharma Inc, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Ren
authors.forename: Jonas
authors.initials: J
authors.lastname: Grina
authors.forename: David
authors.initials: D
authors.lastname: Moreno
authors.forename: James F
authors.initials: JF
authors.lastname: Blake
authors.forename: John J
authors.initials: JJ
authors.lastname: Gaudino
authors.forename: Rustam
authors.initials: R
authors.lastname: Garrey
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Metcalf
authors.forename: Michael
authors.initials: M
authors.lastname: Burkard
authors.forename: Matthew
authors.initials: M
authors.lastname: Martinson
authors.forename: Kevin
authors.initials: K
authors.lastname: Rasor
authors.forename: Huifen
authors.initials: H
authors.lastname: Chen
authors.forename: Brian
authors.initials: B
authors.lastname: Dean
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gould
authors.forename: Patricia
authors.initials: P
authors.lastname: Pacheco
authors.forename: Sheerin
authors.initials: S
authors.lastname: Shahidi-Latham
authors.forename: Jianping
authors.initials: J
authors.lastname: Yin
authors.forename: Kristina
authors.initials: K
authors.lastname: West
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.forename: John G
authors.initials: JG
authors.lastname: Moffat
authors.forename: Jacob B
authors.initials: JB
authors.lastname: Schwarz
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D054852:Small Molecule Libraries; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3