Recent Progress in Histone Demethylase Inhibitors.

There is increasing interest in targeting histone N-methyl-lysine demethylases (KDMs) with small molecules both for the generation of probes for target exploration and for therapeutic purposes. Here we update on previous reviews on the inhibition of the lysine-specific demethylases (LSDs or KDM1s) and JmjC families of N-methyl-lysine demethylases (JmjC KDMs, KDM2-7), focusing on the academic and patent literature from 2014 to date. We also highlight recent biochemical, biological, and structural studies which are relevant to KDM inhibitor development.

[1]  Sheng-yong Yang,et al.  Synthesis and biological evaluation of novel (E)-N'-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides as potent LSD1 inhibitors. , 2016, Bioorganic & medicinal chemistry letters.

[2]  Q. You,et al.  Novel 5-carboxy-8-HQ based histone demethylase JMJD2A inhibitors: introduction of an additional carboxyl group at the C-2 position of quinoline. , 2015, European journal of medicinal chemistry.

[3]  A. Link,et al.  Tetrazolylhydrazides as Selective Fragment‐Like Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A , 2015, ChemMedChem.

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[10]  Luyong Zhang,et al.  Identification of Novel Selective Lysine‐Specific Demethylase 1 (LSD1) Inhibitors Using a Pharmacophore‐Based Virtual Screening Combined with Docking , 2015, Chemical biology & drug design.

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[12]  Yukihiro Itoh,et al.  Histone H3 peptide based LSD1-selective inhibitors. , 2015, Bioorganic & medicinal chemistry letters.

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[14]  Yukihiro Itoh,et al.  Identification of Jumonji AT-Rich Interactive Domain 1A Inhibitors and Their Effect on Cancer Cells. , 2015, ACS medicinal chemistry letters.

[15]  Wei Wang,et al.  Novel Scaffolds of Cell-Active Histone Demethylase Inhibitors Identified from High-Throughput Screening , 2015, Journal of biomolecular screening.

[16]  A. Mai,et al.  Pure enantiomers of benzoylamino-tranylcypromine: LSD1 inhibition, gene modulation in human leukemia cells and effects on clonogenic potential of murine promyelocytic blasts. , 2015, European journal of medicinal chemistry.

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[18]  Yukihiro Itoh,et al.  Design, synthesis, and biological activity of N-alkylated analogue of NCL1, a selective inhibitor of lysine-specific demethylase 1 , 2015 .

[19]  K. Swinger,et al.  A High-Throughput Mass Spectrometry Assay Coupled with Redox Activity Testing Reduces Artifacts and False Positives in Lysine Demethylase Screening , 2015, Journal of biomolecular screening.

[20]  C. Mercurio,et al.  Further insights into the SAR of α-substituted cyclopropylamine derivatives as inhibitors of histone demethylase KDM1A. , 2015, European journal of medicinal chemistry.

[21]  A. Mai,et al.  Pyrrole- and indole-containing tranylcypromine derivatives as novel lysine-specific demethylase 1 inhibitors active on cancer cells , 2015 .

[22]  A. Mai,et al.  Pure Diastereomers of a Tranylcypromine-Based LSD1 Inhibitor: Enzyme Selectivity and In-Cell Studies. , 2015, ACS medicinal chemistry letters.

[23]  Zhijia Wang,et al.  Design, synthesis, and structure-activity relationship of novel LSD1 inhibitors based on pyrimidine-thiourea hybrids as potent, orally active antitumor agents. , 2015, Journal of medicinal chemistry.

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[26]  Sophie T. Williams,et al.  Studies on the catalytic domains of multiple JmjC oxygenases using peptide substrates , 2014, Epigenetics.

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[29]  F. von Delft,et al.  Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor† , 2014, MedChemComm.

[30]  A. Mai,et al.  Synthesis, biological activity and mechanistic insights of 1-substituted cyclopropylamine derivatives: a novel class of irreversible inhibitors of histone demethylase KDM1A. , 2014, European journal of medicinal chemistry.

[31]  P. Cole,et al.  Dissecting the Binding Mode of Low Affinity Phage Display Peptide Ligands to Protein Targets by Hydrogen/Deuterium Exchange Coupled to Mass Spectrometry , 2014, Analytical chemistry.

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[37]  P. Cole,et al.  Substrate- and Cofactor-independent Inhibition of Histone Demethylase KDM4C , 2014, ACS chemical biology.

[38]  M. Calcutt,et al.  Crystal structure of the histone lysine specific demethylase LSD1 complexed with tetrahydrofolate , 2014, Protein science : a publication of the Protein Society.

[39]  Kai-Cheng Hsu,et al.  KDM4B as a Target for Prostate Cancer: Structural Analysis and Selective Inhibition by a Novel Inhibitor , 2014, Journal of medicinal chemistry.

[40]  Shaomeng Wang,et al.  Tranylcypromine Substituted cis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D3 Receptor Antagonists , 2014, Journal of medicinal chemistry.

[41]  R. Janknecht,et al.  Pro-growth role of the JMJD2C histone demethylase in HCT-116 colon cancer cells and identification of curcuminoids as JMJD2 inhibitors. , 2014, American journal of translational research.

[42]  A. Mattevi,et al.  Differential Properties of Transcriptional Complexes Formed by the CoREST Family , 2014, Molecular and Cellular Biology.

[43]  U. Oppermann,et al.  Human UTY(KDM6C) Is a Male-specific Nϵ-Methyl Lysyl Demethylase , 2014, The Journal of Biological Chemistry.

[44]  Hong-min Liu,et al.  Synthesis and biological evaluation of coumarin–1,2,3-triazole–dithiocarbamate hybrids as potent LSD1 inhibitors , 2014 .

[45]  Sean D. Taverna,et al.  A Selective Phenelzine Analogue Inhibitor of Histone Demethylase LSD1 , 2014, ACS chemical biology.

[46]  K. Kavanagh,et al.  Ribosomal Oxygenases are Structurally Conserved from Prokaryotes to Humans , 2014, Nature.

[47]  L. Shapiro,et al.  Hairless is a histone H3K9 demethylase , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[48]  L. Frolova,et al.  Optimal Translational Termination Requires C4 Lysyl Hydroxylation of eRF1 , 2014, Molecular cell.

[49]  D. Maloney,et al.  A Cell-Permeable Ester Derivative of the JmjC Histone Demethylase Inhibitor IOX1 , 2014, ChemMedChem.

[50]  Y. Shidoji,et al.  Inhibition of lysine-specific demethylase 1 by the acyclic diterpenoid geranylgeranoic acid and its derivatives. , 2014, Biochemical and biophysical research communications.

[51]  E. Cundari,et al.  An High-Throughput In Vivo Screening System to Select H3K4-Specific Histone Demethylase Inhibitors , 2014, PloS one.

[52]  E. Novellino,et al.  Pan-histone demethylase inhibitors simultaneously targeting Jumonji C and lysine-specific demethylases display high anticancer activities. , 2014, Journal of medicinal chemistry.

[53]  Isuru R. Kumarasinghe,et al.  Synthesis and evaluation of novel cyclic Peptide inhibitors of lysine-specific demethylase 1. , 2014, ACS medicinal chemistry letters.

[54]  C. Yeh,et al.  CBB1003, a lysine-specific demethylase 1 inhibitor, suppresses colorectal cancer cells growth through down-regulation of leucine-rich repeat-containing G-protein-coupled receptor 5 expression , 2014, Journal of Cancer Research and Clinical Oncology.

[55]  マリオ ヴァラシ,et al.  Cyclopropylamine derivatives useful as inhibitors of histone demethylase KDM1A , 2013 .

[56]  Kristian Helin,et al.  Histone lysine demethylases as targets for anticancer therapy , 2013, Nature Reviews Drug Discovery.

[57]  D. Mobley,et al.  Triazole-dithiocarbamate based selective lysine specific demethylase 1 (LSD1) inactivators inhibit gastric cancer cell growth, invasion, and migration. , 2013, Journal of medicinal chemistry.

[58]  ラベル，マーク,et al.  Histone demethylase inhibitors , 2013 .

[59]  Timothy L. Foley,et al.  Discovery of ML324, a JMJD2 demethylase inhibitor with demonstrated antiviral activity , 2013 .

[60]  Wolfgang Sippl,et al.  Nonpeptidic propargylamines as inhibitors of lysine specific demethylase 1 (LSD1) with cellular activity. , 2013, Journal of medicinal chemistry.

[61]  P. Zhan,et al.  Identification of the KDM2/7 Histone Lysine Demethylase Subfamily Inhibitor and its Antiproliferative Activity , 2013, Journal of medicinal chemistry.

[62]  Qingshan Chang,et al.  Mdig de-represses H19 large intergenic non-coding RNA (lincRNA) by down-regulating H3K9me3 and heterochromatin , 2013, Oncotarget.

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

[64]  U. Oppermann,et al.  Quantitative analysis of histone demethylase probes using fluorescence polarization. , 2013, Journal of medicinal chemistry.

[65]  Sarah G. Bailey,et al.  Protein recognition by short peptide reversible inhibitors of the chromatin-modifying LSD1/CoREST lysine demethylase. , 2013, ACS chemical biology.

[66]  J. Iqbal,et al.  Synthesis and evaluation of 3-amino/guanidine substituted phenyl oxazoles as a novel class of LSD1 inhibitors with anti-proliferative properties. , 2013, Organic & biomolecular chemistry.

[67]  Irene Cantone,et al.  Epigenetic programming and reprogramming during development , 2013, Nature Structural &Molecular Biology.

[68]  Yusuke Nakamura,et al.  Lysyl 5-Hydroxylation, a Novel Histone Modification, by Jumonji Domain Containing 6 (JMJD6)* , 2013, The Journal of Biological Chemistry.

[69]  Michael A McDonough,et al.  Role of the jelly-roll fold in substrate binding by 2-oxoglutarate oxygenases. , 2012, Current opinion in structural biology.

[70]  C. Schofield,et al.  Mechanisms of human histone and nucleic acid demethylases. , 2012, Current opinion in chemical biology.

[71]  C. Robinson,et al.  Oxygenase-catalyzed ribosome hydroxylation occurs in prokaryotes and humans. , 2012, Nature chemical biology.

[72]  N. Nath,et al.  Identification and characterization of small molecule inhibitors of a plant homeodomain finger. , 2012, Biochemistry.

[73]  R. Abagyan,et al.  A metal-based inhibitor of tumor necrosis factor-α. , 2012, Angewandte Chemie.

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[76]  M. Dawson,et al.  Cancer Epigenetics: From Mechanism to Therapy , 2012, Cell.

[77]  Kristian Helin,et al.  Molecular mechanisms and potential functions of histone demethylases , 2012, Nature Reviews Molecular Cell Biology.

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[79]  U. Oppermann,et al.  Linking of 2-oxoglutarate and substrate binding sites enables potent and highly selective inhibition of JmjC histone demethylases. , 2012, Angewandte Chemie.

[80]  Yunlong He,et al.  Targeting protein lysine methylation and demethylation in cancers. , 2012, Acta biochimica et biophysica Sinica.

[81]  Akane Kawamura,et al.  Inhibition of 2‐Oxoglutarate Dependent Oxygenases , 2011 .

[82]  Hualiang Jiang,et al.  Catalytic Mechanism Investigation of Lysine-Specific Demethylase 1 (LSD1): A Computational Study , 2011, PloS one.

[83]  L. Olsen,et al.  Targeting histone lysine demethylases by truncating the histone 3 tail to obtain selective substrate-based inhibitors. , 2011, Angewandte Chemie.

[84]  C. Schofield,et al.  Inhibition of 2-oxoglutarate dependent oxygenases. , 2011, Chemical Society reviews.

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[86]  A. Ganesan,et al.  Enantioselective synthesis of tranylcypromine analogues as lysine demethylase (LSD1) inhibitors. , 2011, Bioorganic & medicinal chemistry.

[87]  K. Helin,et al.  Inhibitors of histone demethylases. , 2011, Bioorganic & medicinal chemistry.

[88]  A. Mai,et al.  Targeting Histone Demethylases: A New Avenue for the Fight against Cancer. , 2011, Genes & cancer.

[89]  Bharat B. Aggarwal,et al.  Epigenetic changes induced by curcumin and other natural compounds , 2011, Genes & Nutrition.

[90]  Monica Mantri,et al.  The 2‐Oxoglutarate‐Dependent Oxygenase JMJD6 Catalyses Oxidation of Lysine Residues to give 5S‐Hydroxylysine Residues , 2011, Chembiochem : a European journal of chemical biology.

[91]  P. Ratcliffe,et al.  Factor-inhibiting hypoxia-inducible factor (FIH) catalyses the post-translational hydroxylation of histidinyl residues within ankyrin repeat domains , 2011, The FEBS journal.

[92]  Andrew J. Bannister,et al.  Regulation of chromatin by histone modifications , 2011, Cell Research.

[93]  Xiaodong Cheng,et al.  Structural basis for human PHF2 Jumonji domain interaction with metal ions. , 2011, Journal of molecular biology.

[94]  Hongtao Yu,et al.  Structural insights into histone lysine demethylation. , 2010, Current opinion in structural biology.

[95]  A. Jadhav,et al.  Quantitative High-Throughput Screening Identifies 8-Hydroxyquinolines as Cell-Active Histone Demethylase Inhibitors , 2010, PloS one.

[96]  J. Hale,et al.  Prolyl hydroxylase domain-containing protein inhibitors as stabilizers of hypoxia-inducible factor: small molecule-based therapeutics for anemia , 2010, Expert opinion on therapeutic patents.

[97]  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.

[98]  R. Klose,et al.  PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an N-dimethyl lysine demethylase , 2009 .

[99]  H. Yasuda,et al.  Regulation of the osteoblast-specific transcription factor Osterix by NO66, a Jumonji family histone demethylase , 2009, The EMBO journal.

[100]  Yang Shi,et al.  Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases , 2010, Nature Structural &Molecular Biology.

[101]  Wolfgang Sippl,et al.  The Emerging Therapeutic Potential of Histone Methyltransferase and Demethylase Inhibitors , 2009, ChemMedChem.

[102]  P. Ratcliffe,et al.  FIH‐Dependent Asparaginyl Hydroxylation of Ankyrin Repeat Domain‐Containing Proteins , 2009, Annals of the New York Academy of Sciences.

[103]  M. Mann,et al.  Jmjd6 Catalyses Lysyl-Hydroxylation of U2AF65, a Protein Associated with RNA Splicing , 2009, Science.

[104]  Y. Rojanasakul,et al.  Lung cancer-associated JmjC domain protein mdig suppresses formation of tri-methyl lysine 9 of histone H3 , 2009, Cell cycle.

[105]  Kristian Helin,et al.  The emerging functions of histone demethylases. , 2008, Current opinion in genetics & development.

[106]  T. Veenstra,et al.  Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases , 2007, Proceedings of the National Academy of Sciences.

[107]  Yingming Zhao,et al.  JMJD6 Is a Histone Arginine Demethylase , 2007, Science.

[108]  Howard Y. Chang,et al.  A histone H3 lysine 27 demethylase regulates animal posterior development , 2007, Nature.

[109]  F. Forneris,et al.  Structural Basis of LSD1-CoREST Selectivity in Histone H3 Recognition* , 2007, Journal of Biological Chemistry.

[110]  M. Machius,et al.  Structural basis for the inhibition of the LSD1 histone demethylase by the antidepressant trans-2-phenylcyclopropylamine. , 2007, Biochemistry.

[111]  A. Rao,et al.  The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation , 2007, Nature.

[112]  P. Ratcliffe,et al.  Posttranslational hydroxylation of ankyrin repeats in IκB proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH) , 2006, Proceedings of the National Academy of Sciences.

[113]  Yi Zhang,et al.  JmjC-domain-containing proteins and histone demethylation , 2006, Nature Reviews Genetics.

[114]  Z. Otwinowski,et al.  Structural basis for CoREST-dependent demethylation of nucleosomes by the human LSD1 histone demethylase. , 2006, Molecular cell.

[115]  Cyrus Martin,et al.  The diverse functions of histone lysine methylation , 2005, Nature Reviews Molecular Cell Biology.

[116]  C. Schwartz,et al.  Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate , 2005, Journal of Medical Genetics.

[117]  F. Lan,et al.  Regulation of LSD1 histone demethylase activity by its associated factors. , 2005, Molecular cell.

[118]  Min Gyu Lee,et al.  An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation , 2005, Nature.

[119]  Antoine H. F. M. Peters,et al.  LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription , 2005, Nature.

[120]  K. Robertson.  DNA methylation and human disease , 2005, Nature Reviews Genetics.

[121]  Peter Cheung,et al.  Epigenetic regulation by histone methylation and histone variants. , 2005, Molecular endocrinology.

[122]  Yang Shi,et al.  Histone Demethylation Mediated by the Nuclear Amine Oxidase Homolog LSD1 , 2004, Cell.

[123]  Paul Tempst,et al.  Histone Deimination Antagonizes Arginine Methylation , 2004, Cell.

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[125]  Robert P. Hausinger,et al.  Fe(II)/α-Ketoglutarate-Dependent Hydroxylases and Related Enzymes , 2004 .

[126]  Christopher J Schofield,et al.  Hypoxia-inducible Factor (HIF) Asparagine Hydroxylase Is Identical to Factor Inhibiting HIF (FIH) and Is Related to the Cupin Structural Family* , 2002, The Journal of Biological Chemistry.

[127]  D. Peet,et al.  FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. , 2002, Genes & development.

[128]  D. Reinberg,et al.  Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. , 2001, Genes & development.

[129]  Y. Nakamura,et al.  Identification of a novel gene, GASC1, within an amplicon at 9p23-24 frequently detected in esophageal cancer cell lines. , 2000, Cancer research.

[130]  W. Paik,et al.  Enzymatic demethylation of calf thymus histones. , 1973, Biochemical and biophysical research communications.