title: Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 2. Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives.
abstract: Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., 1), further optimization led to the identification of non-carboxylate inhibitors derived from pyrido[3,4-d]pyrimidin-4(3H)-one. A number of exemplars such as compound 41 possess interesting activity profiles in KDM4C and KDM5C biochemical and target-specific, cellular mechanistic assays.
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Westaway
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Alex G S
authors.initials: AG
authors.lastname: Preston
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Barker
authors.affiliation: Platform Technology and Sciences, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Fiona
authors.initials: F
authors.lastname: Brown
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Brown
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Matthew
authors.initials: M
authors.lastname: Campbell
authors.affiliation: Platform Technology and Sciences, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Chun-wa
authors.initials: CW
authors.lastname: Chung
authors.affiliation: Cellzome GmbH, a GSK Company , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Gerard
authors.initials: G
authors.lastname: Drewes
authors.affiliation: Platform Technology and Sciences, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Robert
authors.initials: R
authors.lastname: Eagle
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Neil
authors.initials: N
authors.lastname: Garton
authors.affiliation: Platform Technology and Sciences, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Laurie
authors.initials: L
authors.lastname: Gordon
authors.affiliation: Platform Technology and Sciences, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Carl
authors.initials: C
authors.lastname: Haslam
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hayhow
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Humphreys
authors.affiliation: Cellzome GmbH, a GSK Company , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Gerard
authors.initials: G
authors.lastname: Joberty
authors.affiliation: Platform Technology and Sciences, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Roy
authors.initials: R
authors.lastname: Katso
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Laurens
authors.initials: L
authors.lastname: Kruidenier
authors.affiliation: Platform Technology and Sciences, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Melanie
authors.initials: M
authors.lastname: Leveridge
authors.affiliation: Platform Technology and Sciences, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Michelle
authors.initials: M
authors.lastname: Pemberton
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Inma
authors.initials: I
authors.lastname: Rioja
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Gail A
authors.initials: GA
authors.lastname: Seal
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Tracy
authors.initials: T
authors.lastname: Shipley
authors.affiliation: Platform Technology and Sciences, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Onkar
authors.initials: O
authors.lastname: Singh
authors.affiliation: Department of Pure and Applied Chemistry, WestCHEM Research School, University of Strathclyde , Glasgow G1 1XL, U.K.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Suckling
authors.affiliation: Platform Technology and Sciences, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Joanna
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Platform Technology and Sciences, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Pamela
authors.initials: P
authors.lastname: Thomas
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lee
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
mesh_terms: D002460:Cell Line; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011744:Pyrimidinones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; C413655:KDM4C protein, human; D011744:Pyrimidinones; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C521694:KDM4D protein, human; C086877:KDM5C protein, human