title: Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development.
abstract: The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Described herein is the discovery and characterization of GDC-0994 (22), an orally bioavailable small molecule inhibitor selective for ERK kinase activity.
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: James F
authors.initials: JF
authors.lastname: Blake
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Burkard
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Chan
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Huifen
authors.initials: H
authors.lastname: Chen
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Kang-Jye
authors.initials: KJ
authors.lastname: Chou
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Dolores
authors.initials: D
authors.lastname: Diaz
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Danette A
authors.initials: DA
authors.lastname: Dudley
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Gaudino
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gould
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Jonas
authors.initials: J
authors.lastname: Grina
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hunsaker
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Lichuan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Martinson
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: David
authors.initials: D
authors.lastname: Moreno
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Lars
authors.initials: L
authors.lastname: Mueller
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Orr
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: Pacheco
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Ann
authors.initials: A
authors.lastname: Qin
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Rasor
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Ren
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Kirk
authors.initials: K
authors.lastname: Robarge
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Sheerin
authors.initials: S
authors.lastname: Shahidi-Latham
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Stults
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Francis
authors.initials: F
authors.lastname: Sullivan
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jianping
authors.initials: J
authors.lastname: Yin
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Aihe
authors.initials: A
authors.lastname: Zhou
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: John
authors.initials: J
authors.lastname: Moffat
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jacob B
authors.initials: JB
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C000619637:ravoxertinib