2. Academic Validation
  3. 8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors

8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors

  • J Med Chem. 2016 Feb 25;59(4):1388-409. doi: 10.1021/acs.jmedchem.5b01635.
Vassilios Bavetsias 1,  Rachel M Lanigan 1,  Gian Filippo Ruda 2 3,  Butrus Atrash 1,  Mark G McLaughlin 1,  Anthony Tumber 2 3,  N Yi Mok 1,  Yann-Vaï Le Bihan 1,  Sally Dempster 1,  Katherine J Boxall 1,  Fiona Jeganathan 1,  Stephanie B Hatch 2 3,  Pavel Savitsky 2,  Srikannathasan Velupillai 2,  Tobias Krojer 2,  Katherine S England 2 3,  Jimmy Sejberg 1,  Ching Thai 1,  Adam Donovan 1,  Akos Pal 1,  Giuseppe Scozzafava 2 3,  James M Bennett 2 3,  Akane Kawamura 4,  Catrine Johansson 2 5,  Aleksandra Szykowska 2,  Carina Gileadi 2,  Nicola A Burgess-Brown 2,  Frank von Delft 2 6 7,  Udo Oppermann 2 5,  Zoe Walters 8,  Janet Shipley 8,  Florence I Raynaud 1,  Susan M Westaway 9,  Rab K Prinjha 9,  Oleg Fedorov 2 3,  Rosemary Burke 1,  Christopher J Schofield 4,  Isaac M Westwood 1,  Chas Bountra 2,  Susanne Müller 2 3,  Rob L M van Montfort 1,  Paul E Brennan 2 3,  Julian Blagg 1
Affiliations

Affiliations

  • 1 Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
  • 2 Structural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
  • 3 Target Discovery Institute (TDI), Nuffield Department of Medicine, University of Oxford , NDMRB Roosevelt Drive, Oxford OX3 7FZ, U.K.
  • 4 Chemistry Research Laboratory, University of Oxford , Mansfield Road, Oxford OX1 3TA, U.K.
  • 5 Botnar Research Centre, NIHR Oxford Biomedical Research Unit , Oxford OX3 7LD, U.K.
  • 6 Diamond Light Source (DLS), Harwell Science and Innovation Campus , Didcot OX11 0DE, U.K.
  • 7 Department of Biochemistry, University of Johannesburg , Auckland Park 2006, South Africa.
  • 8 Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research , London SM2 5NG, U.K.
  • 9 Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
PMID: 26741168 DOI: 10.1021/acs.jmedchem.5b01635
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.

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