title: 8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors.
abstract: We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Bavetsias
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Lanigan
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute (TDI), Nuffield Department of Medicine, University of Oxford , NDMRB Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Gian Filippo
authors.initials: GF
authors.lastname: Ruda
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Butrus
authors.initials: B
authors.lastname: Atrash
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Mark G
authors.initials: MG
authors.lastname: McLaughlin
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute (TDI), Nuffield Department of Medicine, University of Oxford , NDMRB Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Anthony
authors.initials: A
authors.lastname: Tumber
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: N Yi
authors.initials: NY
authors.lastname: Mok
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Yann-Vaï
authors.initials: YV
authors.lastname: Le Bihan
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Sally
authors.initials: S
authors.lastname: Dempster
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Boxall
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Fiona
authors.initials: F
authors.lastname: Jeganathan
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute (TDI), Nuffield Department of Medicine, University of Oxford , NDMRB Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Hatch
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Pavel
authors.initials: P
authors.lastname: Savitsky
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Srikannathasan
authors.initials: S
authors.lastname: Velupillai
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Tobias
authors.initials: T
authors.lastname: Krojer
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute (TDI), Nuffield Department of Medicine, University of Oxford , NDMRB Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: England
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Sejberg
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Ching
authors.initials: C
authors.lastname: Thai
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Adam
authors.initials: A
authors.lastname: Donovan
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Akos
authors.initials: A
authors.lastname: Pal
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute (TDI), Nuffield Department of Medicine, University of Oxford , NDMRB Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Scozzafava
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute (TDI), Nuffield Department of Medicine, University of Oxford , NDMRB Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: James M
authors.initials: JM
authors.lastname: Bennett
authors.affiliation: Chemistry Research Laboratory, University of Oxford , Mansfield Road, Oxford OX1 3TA, U.K.
authors.forename: Akane
authors.initials: A
authors.lastname: Kawamura
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.|Botnar Research Centre, NIHR Oxford Biomedical Research Unit , Oxford OX3 7LD, U.K.
authors.forename: Catrine
authors.initials: C
authors.lastname: Johansson
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Szykowska
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Carina
authors.initials: C
authors.lastname: Gileadi
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Burgess-Brown
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.|Diamond Light Source (DLS), Harwell Science and Innovation Campus , Didcot OX11 0DE, U.K.|Department of Biochemistry, University of Johannesburg , Auckland Park 2006, South Africa.
authors.forename: Frank
authors.initials: F
authors.lastname: von Delft
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.|Botnar Research Centre, NIHR Oxford Biomedical Research Unit , Oxford OX3 7LD, U.K.
authors.forename: Udo
authors.initials: U
authors.lastname: Oppermann
authors.affiliation: Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research , London SM2 5NG, U.K.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Walters
authors.affiliation: Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research , London SM2 5NG, U.K.
authors.forename: Janet
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authors.lastname: Shipley
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
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: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute (TDI), Nuffield Department of Medicine, University of Oxford , NDMRB Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Burke
authors.affiliation: Chemistry Research Laboratory, University of Oxford , Mansfield Road, Oxford OX1 3TA, U.K.
authors.forename: Christopher J
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authors.lastname: Schofield
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Isaac M
authors.initials: IM
authors.lastname: Westwood
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Chas
authors.initials: C
authors.lastname: Bountra
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute (TDI), Nuffield Department of Medicine, University of Oxford , NDMRB Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Rob L M
authors.initials: RL
authors.lastname: van Montfort
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute (TDI), Nuffield Department of Medicine, University of Oxford , NDMRB Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Brennan
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
authors.forename: Julian
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authors.lastname: Blagg
mesh_terms: D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011744:Pyrimidinones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D011744:Pyrimidinones; D012097:Repressor Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C521694:KDM4D protein, human; C119611:KDM5B protein, human; C494424:KDM4A protein, human