J Med Chem. 2016 Feb 25;59(4):1388-409. doi: 10.1021/acs.jmedchem.5b01635. Epub 2016 Jan 7.

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

Bavetsias V¹, Lanigan RM¹, Ruda GF^2,³, Atrash B¹, McLaughlin MG¹, Tumber A^2,³, Mok NY¹, Le Bihan YV¹, Dempster S¹, Boxall KJ¹, Jeganathan F¹, Hatch SB^2,³, Savitsky P², Velupillai S², Krojer T², England KS^2,³, Sejberg J¹, Thai C¹, Donovan A¹, Pal A¹, Scozzafava G^2,³, Bennett JM^2,³, Kawamura A⁴, Johansson C^2,⁵, Szykowska A², Gileadi C², Burgess-Brown NA², von Delft F^2,^6,⁷, Oppermann U^2,⁵, Walters Z⁸, Shipley J⁸, Raynaud FI¹, Westaway SM⁹, Prinjha RK⁹, Fedorov O^2,³, Burke R¹, Schofield CJ⁴, Westwood IM¹, Bountra C², Müller S^2,³, van Montfort RL¹, Brennan PE^2,³, Blagg J¹.

Author information

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.

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.