Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives.

Optimization of KDM6B (JMJD3) HTS hit 12 led to the identification of 3-((furan-2-ylmethyl)amino)pyridine-4-carboxylic acid 34 and 3-(((3-methylthiophen-2-yl)methyl)amino)pyridine-4-carboxylic acid 39 that are inhibitors of the KDM4 (JMJD2) family of histone lysine demethylases. Compounds 34 and 39 possess activity, IC50 ≤ 100 nM, in KDM4 family biochemical (RFMS) assays with ≥ 50-fold selectivity against KDM6B and activity in a mechanistic KDM4C cell imaging assay (IC50 = 6-8 μM). Compounds 34 and 39 are also potent inhibitors of KDM5C (JARID1C) (RFMS IC50 = 100-125 nM).

[1]  David M. Wilson,et al.  Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 2. Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives. , 2016, Journal of medicinal chemistry.

[2]  Gonzalo Colmenarejo,et al.  Identification and Characterization of Hundreds of Potent and Selective Inhibitors of Trypanosoma brucei Growth from a Kinase-Targeted Library Screening Campaign , 2014, PLoS neglected tropical diseases.

[3]  A. Tarakhovsky,et al.  Chromatin targeting drugs in cancer and immunity , 2013, Genes & development.

[4]  R. Klose,et al.  5-Carboxy-8-hydroxyquinoline is a Broad Spectrum 2-Oxoglutarate Oxygenase Inhibitor which Causes Iron Translocation. , 2013, Chemical science.

[5]  J. Whetstine,et al.  Histone lysine methylation dynamics: establishment, regulation, and biological impact. , 2012, Molecular cell.

[6]  Christopher J. Schofield,et al.  A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response , 2012, Nature.

[7]  R. Klose,et al.  Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases. , 2012, Journal of medicinal chemistry.

[8]  C. Bountra,et al.  Epigenetic protein families: a new frontier for drug discovery , 2012, Nature Reviews Drug Discovery.

[9]  Melanie V. Leveridge,et al.  Enabling Lead Discovery for Histone Lysine Demethylases by High-Throughput RapidFire Mass Spectrometry , 2012, Journal of biomolecular screening.

[10]  S. Schreiber,et al.  A selective inhibitor and probe of the cellular functions of Jumonji C domain-containing histone demethylases. , 2011, Journal of the American Chemical Society.

[11]  T. Heightman,et al.  Inhibition of Histone Demethylases by 4‐Carboxy‐2,2′‐Bipyridyl Compounds , 2011, ChemMedChem.

[12]  T. Heightman,et al.  Inhibition of the histone demethylase JMJD2E by 3-substituted pyridine 2,4-dicarboxylates. , 2011, Organic & biomolecular chemistry.

[13]  Makoto Hasegawa,et al.  Design, synthesis, enzyme-inhibitory activity, and effect on human cancer cells of a novel series of jumonji domain-containing protein 2 histone demethylase inhibitors. , 2010, Journal of medicinal chemistry.

[14]  David M. Wilson,et al.  Epigenetic control of the immune system: histone demethylation as a target for drug discovery. , 2010, Drug discovery today. Technologies.

[15]  Christopher J. Schofield,et al.  Selective Inhibitors of the JMJD2 Histone Demethylases: Combined Nondenaturing Mass Spectrometric Screening and Crystallographic Approaches† , 2010, Journal of medicinal chemistry.

[16]  C. Schofield,et al.  Inhibition of the histone lysine demethylase JMJD2A by ejection of structural Zn(II). , 2009, Chemical communications.

[17]  Robert A. Copeland,et al.  Protein methyltransferases as a target class for drug discovery , 2009, Nature Reviews Drug Discovery.

[18]  Yukihiro Itoh,et al.  Synthesis and activity of N-oxalylglycine and its derivatives as Jumonji C-domain-containing histone lysine demethylase inhibitors. , 2009, Bioorganic & medicinal chemistry letters.

[19]  U. Oppermann,et al.  Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases. , 2008, Journal of medicinal chemistry.

[20]  Juri Rappsilber,et al.  The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3 , 2006, Nature.

[21]  P. Carmeliet,et al.  Emerging novel functions of the oxygen-sensing prolyl hydroxylase domain enzymes. , 2013, Trends in biochemical sciences.