Targeting histone methylation for cancer therapy: enzymes, inhibitors, biological activity and perspectives

Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia

(2016) Zizhen Feng et al.   Journal of Hematology & Oncology

Prognostic Significance of EZH2 Expression in Non-Small Cell Lung Cancer: A Meta-analysis

(2016) Xinhua Wang et al.   Scientific Reports

A Potent, Selective, and Cell-Active Inhibitor of Human Type I Protein Arginine Methyltransferases

(2015) Mohammad S. Eram et al.   ACS Chemical Biology

A Potent, Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3)

(2015) H. Ümit Kaniskan et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC

(2015) Helai P. Mohammad et al.   CANCER CELL

Advances in the development of histone lysine demethylase inhibitors

(2015) Tamara Maes et al.   CURRENT OPINION IN PHARMACOLOGY

Histone demethylases in chromatin biology and beyond

(2015) E. Dimitrova et al.   EMBO REPORTS

LLY-507, a Cell-active, Potent, and Selective Inhibitor of Protein-lysine Methyltransferase SMYD2

(2015) Hannah Nguyen et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

DNA methyltransferase 1 functions through C/ebpa to maintain hematopoietic stem and progenitor cells in zebrafish

(2015) Xiaohui Liu et al.   Journal of Hematology & Oncology

Role of DNA methylation in renal cell carcinoma

(2015) Niraj Shenoy et al.   Journal of Hematology & Oncology

Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds

(2015) Fangrui Wu et al.   JOURNAL OF MEDICINAL CHEMISTRY

3-(Piperidin-4-ylmethoxy)pyridine Containing Compounds Are Potent Inhibitors of Lysine Specific Demethylase 1

(2015) Fangrui Wu et al.   JOURNAL OF MEDICINAL CHEMISTRY

A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models

(2015) Elayne Chan-Penebre et al.   Nature Chemical Biology

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

(2015) Ke Liu et al.   PHARMACOLOGY & THERAPEUTICS

Targeting histone lysine methylation in cancer

(2015) John McGrath et al.   PHARMACOLOGY & THERAPEUTICS

Aryl Pyrazoles as Potent Inhibitors of Arginine Methyltransferases: Identification of the First PRMT6 Tool Compound

(2015) Lorna H. Mitchell et al.   ACS Medicinal Chemistry Letters

The polycomb group protein EZH2 is a novel therapeutic target in tongue cancer

(2015) Zhongwu li et al.   Oncotarget

Inhibition of histone H3K79 methylation selectively inhibits proliferation, self-renewal and metastatic potential of breast cancer

(2015) Li Zhang et al.   Oncotarget

A Selective Phenelzine Analogue Inhibitor of Histone Demethylase LSD1

(2014) Polina Prusevich et al.   ACS Chemical Biology

EZH2 Inhibitor Efficacy in Non-Hodgkin’s Lymphoma Does Not Require Suppression of H3K27 Monomethylation

(2014) William D. Bradley et al.   CHEMISTRY & BIOLOGY

Selective Inhibition of Mutant Isocitrate Dehydrogenase 1 (IDH1) via Disruption of a Metal Binding Network by an Allosteric Small Molecule

(2014) Gejing Deng et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levels

(2014) Amy Guillaumet-Adkins et al.   Journal of Hematology & Oncology

CBFB-MYH11 hypomethylation signature and PBX3 differential methylation revealed by targeted bisulfite sequencing in patients with acute myeloid leukemia

(2014) Hana Hájková et al.   Journal of Hematology & Oncology

c-FLIP is involved in tumor progression of peripheral T-cell lymphoma and targeted by histone deacetylase inhibitors

(2014) Zhong Zheng et al.   Journal of Hematology & Oncology

Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases: Synthesis, Structure–Activity Relationship, and Selective Antitumor Activity

(2014) Zhen Liu et al.   JOURNAL OF MEDICINAL CHEMISTRY

Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells

(2014) W Fiskus et al.   LEUKEMIA

Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in EZH2-Mutant Non-Hodgkin Lymphoma

(2014) S. K. Knutson et al.   MOLECULAR CANCER THERAPEUTICS

Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia

(2014) Fang Cao et al.   MOLECULAR CELL

Epigenetic targets and drug discovery

(2014) Yanli Liu et al.   PHARMACOLOGY & THERAPEUTICS

DOT1L Inhibition Sensitizes MLL-Rearranged AML to Chemotherapy

(2014) Wei Liu et al.   PLoS One

Discovery and Development of Potent and Selective Inhibitors of Histone Methyltransferase G9a

(2014) Ramzi F. Sweis et al.   ACS Medicinal Chemistry Letters

An Orally Bioavailable Chemical Probe of the Lysine Methyltransferases EZH2 and EZH1

(2013) Kyle D. Konze et al.   ACS Chemical Biology

Bromo-deaza-SAH: A potent and selective DOT1L inhibitor

(2013) Wenyu Yu et al.   BIOORGANIC & MEDICINAL CHEMISTRY

Potent inhibition of DOT1L as treatment of MLL-fusion leukemia

(2013) S. R. Daigle et al.   BLOOD

Identification of EZH2 and EZH1 Small Molecule Inhibitors with Selective Impact on Diffuse Large B Cell Lymphoma Cell Growth

(2013) Shivani Garapaty-Rao et al.   CHEMISTRY & BIOLOGY

Triazole–Dithiocarbamate Based Selective Lysine Specific Demethylase 1 (LSD1) Inactivators Inhibit Gastric Cancer Cell Growth, Invasion, and Migration

(2013) Yi-Chao Zheng et al.   JOURNAL OF MEDICINAL CHEMISTRY

High-Throughput Virtual Screening Identifies Novel N′-(1-Phenylethylidene)-benzohydrazides as Potent, Specific, and Reversible LSD1 Inhibitors

(2013) Venkataswamy Sorna et al.   JOURNAL OF MEDICINAL CHEMISTRY

Histone lysine demethylases as targets for anticancer therapy

(2013) Jonas W. Højfeldt et al.   NATURE REVIEWS DRUG DISCOVERY

An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells

(2013) D. Rohle et al.   SCIENCE

Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation

(2013) F. Wang et al.   SCIENCE

Synthesis, activity and metabolic stability of non-ribose containing inhibitors of histone methyltransferase DOT1L

(2013) Lisheng Deng et al.   MedChemComm

Crystallographic Investigation and Selective Inhibition of Mutant Isocitrate Dehydrogenase

(2013) Baisong Zheng et al.   ACS Medicinal Chemistry Letters

Histone demethylase Lsd1 represses hematopoietic stem and progenitor cell signatures during blood cell maturation

(2013) Marc A Kerenyi et al.   eLife

The Histone Demethylase KDM1A Sustains the Oncogenic Potential of MLL-AF9 Leukemia Stem Cells

(2012) William J. Harris et al.   CANCER CELL

Conformational Adaptation Drives Potent, Selective and Durable Inhibition of the Human Protein Methyltransferase DOT1L

(2012) Aravind Basavapathruni et al.   Chemical Biology & Drug Design

LSD1 inhibition: a therapeutic strategy in cancer?

(2012) James T Lynch et al.   EXPERT OPINION ON THERAPEUTIC TARGETS

Synthesis and Structure–Activity Relationship Investigation of Adenosine-Containing Inhibitors of Histone Methyltransferase DOT1L

(2012) Justin L. Anglin et al.   JOURNAL OF MEDICINAL CHEMISTRY

High-Affinity, Small-Molecule Peptidomimetic Inhibitors of MLL1/WDR5 Protein–Protein Interaction

(2012) Hacer Karatas et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

(2012) A Sprüssel et al.   LEUKEMIA

Chromatin-modifying enzymes as modulators of reprogramming

(2012) Tamer T. Onder et al.   NATURE

IDH mutation impairs histone demethylation and results in a block to cell differentiation

(2012) Chao Lu et al.   NATURE

IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype

(2012) Sevin Turcan et al.   NATURE

A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response

(2012) Laurens Kruidenier et al.   NATURE

EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations

(2012) Michael T. McCabe et al.   NATURE

The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;NrasG12D acute myeloid leukemia

(2012) J Shi et al.   ONCOGENE

Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27)

(2012) M. T. McCabe et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing

(2012) J. G. Lohr et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumor 2-HG in Vivo

(2012) Janeta Popovici-Muller et al.   ACS Medicinal Chemistry Letters

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

(2012) Wenyu Yu et al.   Nature Communications

Brain-Penetrant LSD1 Inhibitors Can Block Memory Consolidation

(2011) Ramesh Neelamegam et al.   ACS Chemical Neuroscience

Structural basis for CARM1 inhibition by indole and pyrazole inhibitors

(2011) John S. Sack et al.   BIOCHEMICAL JOURNAL

Selective Killing of Mixed Lineage Leukemia Cells by a Potent Small-Molecule DOT1L Inhibitor

(2011) Scott R. Daigle et al.   CANCER CELL

Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases

(2011) Wei Xu et al.   CANCER CELL

Coexistence of LMPP-like and GMP-like Leukemia Stem Cells in Acute Myeloid Leukemia

(2011) Nicolas Goardon et al.   CANCER CELL

Essential role of DOT1L in maintaining normal adult hematopoiesis

(2011) Anh T Nguyen et al.   CELL RESEARCH

Chemogenetic Analysis of Human Protein Methyltransferases

(2011) Victoria M. Richon et al.   Chemical Biology & Drug Design

Polycomb genes and cancer: Time for clinical application?

(2011) Francesco Crea et al.   CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY

The Y641C mutation of EZH2 alters substrate specificity for histone H3 lysine 27 methylation states

(2011) Tim J. Wigle et al.   FEBS LETTERS

DOT1L regulates dystrophin expression and is critical for cardiac function

(2011) A. T. Nguyen et al.   GENES & DEVELOPMENT

The diverse functions of Dot1 and H3K79 methylation

(2011) A. T. Nguyen et al.   GENES & DEVELOPMENT

Deficiency of H3K79 Histone Methyltransferase Dot1-like Protein (DOT1L) Inhibits Cell Proliferation

(2011) Wootae Kim et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Lysine Demethylases Inhibitors

(2011) Takayoshi Suzuki et al.   JOURNAL OF MEDICINAL CHEMISTRY

IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours

(2011) M Fernanda Amary et al.   JOURNAL OF PATHOLOGY

Selective Inhibitors of Histone Methyltransferase DOT1L: Design, Synthesis, and Crystallographic Studies

(2011) Yuan Yao et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma

(2011) Ryan D. Morin et al.   NATURE

A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells

(2011) Masoud Vedadi et al.   Nature Chemical Biology

Structural Basis of Substrate Methylation and Inhibition of SMYD2

(2011) Andrew D. Ferguson et al.   STRUCTURE

A role for DOT1L inMLL-rearranged leukemias

(2011) Kathrin M Bernt et al.   Epigenomics

Early mammalian erythropoiesis requires the Dot1L methyltransferase

(2010) Y. Feng et al.   BLOOD

Copy number variation and cytidine analogue cytotoxicity: A genome-wide association approach

(2010) Krishna R Kalari et al.   BMC GENOMICS

The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate

(2010) Patrick S. Ward et al.   CANCER CELL

Identification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma

(2010) Houtan Noushmehr et al.   CANCER CELL

Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation

(2010) Maria E. Figueroa et al.   CANCER CELL

MLL-AF9-Induced Leukemogenesis Requires Coexpression of the Wild-Type Mll Allele

(2010) Austin T. Thiel et al.   CANCER CELL

Demethylation of RB Regulator MYPT1 by Histone Demethylase LSD1 Promotes Cell Cycle Progression in Cancer Cells

(2010) H.-S. Cho et al.   CANCER RESEARCH

Targeting DOT1L action and interactions in leukemia: the role of DOT1L in transformation and development

(2010) Evan R Barry et al.   EXPERT OPINION ON THERAPEUTIC TARGETS

Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom)

(2010) M. Mohan et al.   GENES & DEVELOPMENT

G9a and Glp Methylate Lysine 373 in the Tumor Suppressor p53

(2010) Jing Huang et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

IDH1andIDH2Gene Mutations Identify Novel Molecular Subsets Within De Novo Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study

(2010) Guido Marcucci et al.   JOURNAL OF CLINICAL ONCOLOGY

Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations

(2010) Stefan Gross et al.   JOURNAL OF EXPERIMENTAL MEDICINE

(Bis)urea and (Bis)thiourea Inhibitors of Lysine-Specific Demethylase 1 as Epigenetic Modulators

(2010) Shiv K. Sharma et al.   JOURNAL OF MEDICINAL CHEMISTRY

Biochemical, Structural, and Biological Evaluation of Tranylcypromine Derivatives as Inhibitors of Histone Demethylases LSD1 and LSD2

(2010) Claudia Binda et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

AFF4, a Component of the ELL/P-TEFb Elongation Complex and a Shared Subunit of MLL Chimeras, Can Link Transcription Elongation to Leukemia

(2010) Chengqi Lin et al.   MOLECULAR CELL

Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin

(2010) Ryan D Morin et al.   NATURE GENETICS

Cancer-associated IDH mutations: biomarker and therapeutic opportunities

(2010) K E Yen et al.   ONCOGENE

An Ash2L/RbBP5 Heterodimer Stimulates the MLL1 Methyltransferase Activity through Coordinated Substrate Interactions with the MLL1 SET Domain

(2010) Fang Cao et al.   PLoS One

Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes

(2010) J. Yang et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas

(2010) C. J. Sneeringer et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Histone demethylases in development and disease

(2010) Marianne Terndrup Pedersen et al.   TRENDS IN CELL BIOLOGY

IDH mutations in glioma and acute myeloid leukemia

(2010) Lenny Dang et al.   TRENDS IN MOLECULAR MEDICINE

Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas

(2009) Christian Hartmann et al.   ACTA NEUROPATHOLOGICA

IDH1 Mutations Are Early Events in the Development of Astrocytomas and Oligodendrogliomas

(2009) Takuya Watanabe et al.   AMERICAN JOURNAL OF PATHOLOGY

Therapeutic targeting of MLL

(2009) M. Liedtke et al.   BLOOD

EZH2 Is Essential for Glioblastoma Cancer Stem Cell Maintenance

(2009) M.-L. Suva et al.   CANCER RESEARCH

Lysine-Specific Demethylase 1 Is Strongly Expressed in Poorly Differentiated Neuroblastoma: Implications for Therapy

(2009) J. H. Schulte et al.   CANCER RESEARCH

Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma

(2009) Shuhei Komatsu et al.   CARCINOGENESIS

Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology

(2009) Soyoung Lim et al.   CARCINOGENESIS

IDH1mutations at residue p.R132 (IDH1R132) occur frequently in high-grade gliomas but not in other solid tumors

(2009) Fonnet E. Bleeker et al.   HUMAN MUTATION

Discovery of a 2,4-Diamino-7-aminoalkoxyquinazoline as a Potent and Selective Inhibitor of Histone Lysine Methyltransferase G9a

(2009) Feng Liu et al.   JOURNAL OF MEDICINAL CHEMISTRY

Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

(2009) Lenny Dang et al.   NATURE

Protein methyltransferases as a target class for drug discovery

(2009) Robert A. Copeland et al.   NATURE REVIEWS DRUG DISCOVERY

Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases

(2009) John R Horton et al.   NATURE STRUCTURAL & MOLECULAR BIOLOGY

IDH1andIDH2Mutations in Gliomas

(2009) Hai Yan et al.   NEW ENGLAND JOURNAL OF MEDICINE

Glioma-Derived Mutations in IDH1 Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1 

(2009) S. Zhao et al.   SCIENCE

Misguided Transcriptional Elongation Causes Mixed Lineage Leukemia

(2009) Dorothee Mueller et al.   PLOS BIOLOGY

Analysis of the IDH1 codon 132 mutation in brain tumors

(2008) Jörg Balss et al.   ACTA NEUROPATHOLOGICA

H3K79 Methylation Profiles Define Murine and Human MLL-AF4 Leukemias

(2008) Andrei V. Krivtsov et al.   CANCER CELL

Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease

(2008) P. A.C. Cloos et al.   GENES & DEVELOPMENT

A Genecentric Human Protein Atlas for Expression Profiles Based on Antibodies

(2008) Lisa Berglund et al.   MOLECULAR & CELLULAR PROTEOMICS

DOT1L/KMT4 Recruitment and H3K79 Methylation Are Ubiquitously Coupled with Gene Transcription in Mammalian Cells

(2008) D. J. Steger et al.   MOLECULAR AND CELLULAR BIOLOGY

Roles of the EZH2 histone methyltransferase in cancer epigenetics

(2008) Jeffrey A. Simon et al.   MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS

Chemical probes for histone-modifying enzymes

(2008) Philip A Cole   Nature Chemical Biology

The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation

(2008) Jing Wang et al.   NATURE GENETICS

Combinatorial patterns of histone acetylations and methylations in the human genome

(2008) Zhibin Wang et al.   NATURE GENETICS

Downregulation of Histone H3 Lysine 9 Methyltransferase G9a Induces Centrosome Disruption and Chromosome Instability in Cancer Cells

(2008) Yutaka Kondo et al.   PLoS One

An Integrated Genomic Analysis of Human Glioblastoma Multiforme

(2008) D. W. Parsons et al.   SCIENCE

The Histone H3K79 Methyltransferase Dot1L Is Essential for Mammalian Development and Heterochromatin Structure

(2008) Brendan Jones et al.   PLoS Genetics

Changes in H3K79 Methylation During Preimplantation Development in Mice

(2007) Masatoshi Ooga et al.   BIOLOGY OF REPRODUCTION