title: Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine inhibitors of Erk2.
abstract: The discovery and optimization of a series of tetrahydropyridopyrimidine based extracellular signal-regulated kinase (Erks) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent and selective inhibition of Erk2 and knockdown of phospho-RSK levels in HepG2 cells and tumor xenografts.
authors.affiliation: Array BioPharma Inc, Boulder, CO 80301, USA. Electronic address: jblake@arraybiopharma.com.
authors.forename: James F
authors.initials: JF
authors.lastname: Blake
authors.affiliation: Array BioPharma Inc, Boulder, CO 80301, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Gaudino
authors.affiliation: Array BioPharma Inc, Boulder, CO 80301, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: De Meese
authors.affiliation: Array BioPharma Inc, Boulder, CO 80301, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Mohr
authors.affiliation: Array BioPharma Inc, Boulder, CO 80301, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Chicarelli
authors.affiliation: Array BioPharma Inc, Boulder, CO 80301, USA.
authors.forename: Hongqi
authors.initials: H
authors.lastname: Tian
authors.affiliation: Array BioPharma Inc, Boulder, CO 80301, USA.
authors.forename: Rustam
authors.initials: R
authors.lastname: Garrey
authors.affiliation: Array BioPharma Inc, Boulder, CO 80301, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Array BioPharma Inc, Boulder, CO 80301, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Siedem
authors.affiliation: Array BioPharma Inc, Boulder, CO 80301, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Welch
authors.affiliation: Array BioPharma Inc, Boulder, CO 80301, USA.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Kolakowski
authors.affiliation: Array BioPharma Inc, Boulder, CO 80301, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Kaus
authors.affiliation: Array BioPharma Inc, Boulder, CO 80301, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Burkard
authors.affiliation: Array BioPharma Inc, Boulder, CO 80301, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Martinson
authors.affiliation: Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990, USA.
authors.forename: Huifen
authors.initials: H
authors.lastname: Chen
authors.affiliation: Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Dean
authors.affiliation: Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990, USA.
authors.forename: Danette A
authors.initials: DA
authors.lastname: Dudley
authors.affiliation: Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gould
authors.affiliation: Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Pacheco
authors.affiliation: Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990, USA.
authors.forename: Sheerin
authors.initials: S
authors.lastname: Shahidi-Latham
authors.affiliation: Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990, USA.
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.affiliation: Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: West
authors.affiliation: Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990, USA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Yin
authors.affiliation: Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990, USA.
authors.forename: John
authors.initials: J
authors.lastname: Moffat
authors.affiliation: Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990, USA.
authors.forename: Jacob B
authors.initials: JB
authors.lastname: Schwarz
mesh_terms: D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: C496331:6-(2,5-dimethoxybenzyl)-5,6,7,8-tetrahydropyrido(2,3-d)pyrimidine-2,4-diamine; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D054852:Small Molecule Libraries; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Erk2 kinase inhibitors; Mek resistance; Structure based drug design