Wolfgang Sippl, PhD, holds the chair in Medicinal Chemistry at the Institute of Pharmacy at the Martin Luther University Halle-Wittenberg. Manfred Jung, PhD, is a full professor for Pharmaceutical Chemistry at the University of Freiburg and the co-chairman of the SFB research project "Medical Epigenetics".

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• Part I Introduction – Epigenetics 11 Epigenetics:Moving Forward 3Lucia Altucci1.1 Why This Enormously Increased Interest? 41.2 Looking Forward to New Avenues of Epigenetics 5Acknowledgments 7References 7Part II General Aspects/Methodologies 112 Structural Biology of Epigenetic Targets: Exploiting Complexity 13Martin Marek, Tajith B. Shaik, and Christophe Romier2.1 Introduction 132.2 DNA Methylases:The DNMT3A–DNMT3L–H3 and DNMT1–USP7 Complexes 142.3 Histone Arginine Methyltransferases:The PRMT5–MEP50 Complex 162.4 Histone Lysine Methyltransferases:The MLL3–RBBP5–ASH2L and the PRC2 Complexes 172.5 Histone Lysine Ubiquitinylases: The PRC1 Complex 212.6 Histone Lysine Deubiquitinylases: The SAGA Deubiquitination Module 222.7 Histone Acetyltransferases:The MSL1 and NUA4 Complexes 242.8 Histone Deacetylases: HDAC1–MTA1 and HDAC3–SMRT Complexes and HDAC6 262.9 Histone Variants and Histone Chaperones: A Complex and Modular Interplay 282.10 ATP-Dependent Remodelers: CHD1, ISWI, SNF2, and the SNF2-Nucleosome Complex 312.11 Epigenetic Readers: Histone Crotonylation Readers and the 53BP1-Nucleosome (H2AK15Ub–H4K20me2) Complex 352.12 Conclusions 37Acknowledgments 38References 383 Computer-based Lead Identification for Epigenetic Targets 45Chiara Luise, Tino Heimburg, Berin Karaman, Dina Robaa, andWolfgang Sippl3.1 Introduction 453.2 Computer-based Methods in Drug Discovery 463.2.1 Pharmacophore-based Methods 463.2.2 QSAR 473.2.3 Docking 473.2.4 Virtual Screening 483.2.5 Binding Free Energy Calculation 493.3 Histone Deacetylases 493.3.1 Zinc-Dependent HDACs 493.3.2 Sirtuins 543.4 Histone Methyltransferases 583.5 Histone Demethylases 613.5.1 LSD1 (KDM1A) 623.5.2 Jumonji Histone Demethylases 643.6 Summary 66Acknowledgments 66References 674 Mass Spectrometry and Chemical Biology in Epigenetics Drug Discovery 79Christian Feller, DavidWeigt, and Carsten Hopf4.1 Introduction: Mass Spectrometry Technology Used in Epigenetic Drug Discovery 794.1.1 Mass SpectrometryWorkflows for the Analysis of Proteins 804.1.2 Mass Spectrometry Imaging 834.2 Target Identification and Selectivity Profiling: Chemoproteomics 854.2.1 Histone Deacetylase and Acetyltransferase Chemoproteomics 874.2.2 Bromodomain Chemoproteomics 884.2.3 Demethylase Chemoproteomics 884.2.4 Methyltransferase Chemoproteomics 894.3 Characterization of Epigenetic Drug Target Complexes and Reader Complexes Contributing to Drug’s Mode of Action 894.3.1 Immunoaffinity Purification of Native Protein Complexes 894.3.2 Immunoaffinity Purification with Antibodies against Epitope Tags 904.3.3 Affinity Enrichment Using Histone Tail Peptides as Bait 914.4 Elucidation of a Drug’s Mode of Action: Analysis of Histone Posttranslational Modifications by MS-Based Proteomics 914.4.1 Histone Modification MS Workflows 924.4.2 Application of Histone MS Workflows to Characterize Epigenetic Drugs 954.5 Challenges and New Trends 974.5.1 Challenges and Trends in MS Analysis of Histone PTMs 974.5.2 High-Throughput Mass Spectrometry-Based Compound Profiling in Epigenetic Drug Discovery 984.5.3 Mass Spectrometry Imaging of Drug Action 98Acknowledgments 99References 995 PeptideMicroarrays for Epigenetic Targets 107Alexandra Schutkowski, Diana Kalbas, Ulf Reimer, andMike Schutkowski5.1 Introduction 1075.2 Applications of Peptide Microarrays for Epigenetic Targets 1105.2.1 Profiling of Substrate Specificities of Histone CodeWriters 1105.2.2 Profiling of Substrate Specificities of Histone Code Erasers 1145.2.3 Profiling of Binding Specificities of PTM-specific Antibodies and Histone Code Readers 1175.2.3.1 Profiling of Specificities of PTM-specific Antibodies 1185.2.3.2 Profiling of Binding Specificities of Histone Code Readers 1195.2.4 Peptide Microarray-based Identification of Upstream Kinases and Phosphorylation Sites for Epigenetic Targets 1215.3 Conclusion and Outlook 124Acknowledgment 124References 1246 Chemical Probes 133Amy Donner, Heather King, Paul E. Brennan, MosesMoustakim, andWilliam J. Zuercher6.1 Chemical Probes Are Privileged Reagents for Biological Research 1336.1.1 Best Practices for the Generation and Selection of Chemical Probes 1346.1.2 Best Practices for Application of Chemical Probes 1366.1.3 Cellular Target Engagement 1376.1.3.1 Fluorescence Recovery after Photobleaching (FRAP) 1386.1.3.2 Affinity Bead-Based Proteomics 1386.1.3.3 Cellular Thermal Shift Assay (CETSA) 1396.1.3.4 Bioluminescence Resonance Energy Transfer 1396.2 Epigenetic Chemical Probes 1416.2.1 Histone Acetylation and Bromodomain Chemical Probes 1416.2.1.1 CBP/p300 Bromodomain Chemical Probes 1446.2.1.2 Future Applications of Bromodomain Chemical Probes 1476.3 Summary 147References 148Part III Epigenetic Target Classes 1537 Inhibitors of the Zinc-Dependent Histone Deacetylases 155Helle M. E. Kristensen, Andreas S. Madsen, and Christian A. Olsen7.1 Introduction: Histone Deacetylases 1557.2 Histone Deacetylase Inhibitors 1587.2.1 Types of Inhibitors 1587.2.2 HDAC Inhibitors in Clinical Use and Development 1607.3 Targeting of HDAC Subclasses 1697.3.1 Class I Inhibitors 1697.3.1.1 HDAC1–3 Inhibitors 1707.3.1.2 HDAC Inhibitors Targeting HDAC8 1737.3.2 Class IIa Inhibitors 1747.3.3 Class IIb 1767.4 Perspectives 177References 1798 Sirtuins as Drug Targets 185Clemens Zwergel, Dante Rotili, Sergio Valente, and Antonello Mai8.1 Introduction 1858.2 Biological Functions of Sirtuins in Physiology and Pathology 1858.3 SIRT Modulators 1888.3.1 SIRT Inhibitors 1888.3.1.1 Small Molecules 1888.3.1.2 Peptides and Pseudopeptides 1918.3.2 SIRT Activators 1918.4 Summary and Conclusions 192References 1939 Selective Small-Molecule Inhibitors of Protein Methyltransferases 201H. Ümit Kaniskan and Jian Jin9.1 Introduction 2019.2 Protein Methylation 2019.3 Lysine Methyltransferases (PKMTs) 2029.4 Inhibitors of PKMTs 2029.4.1 Inhibitors of H3K9 Methyltransferases 2029.4.2 Inhibitors of H3K27 Methyltransferases 2049.4.3 Inhibitors of H3K4 and H3K36 Methyltransferases 2069.4.4 Inhibitors of H4K20 Methyltransferases 2089.4.5 Inhibitors of H3K79 Methyltransferases 2109.5 Protein Arginine Methyltransferases (PRMTs) 2119.5.1 Inhibitors of PRMT1 2119.5.2 Inhibitors of PRMT3 2129.5.3 Inhibitors of CARM1 2139.5.4 Inhibitors of PRMT5 2149.5.5 Inhibitors of PRMT6 2149.6 Concluding Remarks 215References 21510 LSD (Lysine-Specific Demethylase): A Decade-Long Trip from Discovery to Clinical Trials 221Adam Lee, M. Teresa Borrello, and A. Ganesan10.1 Introduction 22110.2 LSDs: Discovery and Mechanistic Features 22310.3 LSD Substrates 22510.4 LSD Function and Dysfunction 22910.5 LSD Inhibitors 23210.5.1 Irreversible Small Molecule LSD Inhibitors from MAO Inhibitors 23310.5.2 Reversible Small Molecule LSD Inhibitors 24110.5.3 Synthetic Macromolecular LSD Inhibitors 24810.6 Summary 251References 25311 JmjC-domain-Containing Histone Demethylases 263Christoffer Højrup, Oliver D. Coleman, John-Paul Bukowski, Rasmus P. Clausen, and Akane Kawamura11.1 Introduction 26311.1.1 The LSD and JmjC Histone Lysine Demethylases 26311.1.2 Histone Lysine Methylation and the JmjC-KDMs 26511.1.3 The JmjC-KDMs in Development and Disease 26611.2 KDM Inhibitor Development Targeting the JmjC Domain 27211.2.1 2-Oxoglutarate Cofactor Mimicking Inhibitors 27311.2.1.1 Emulation of the Chelating α-Keto AcidMoiety in 2OG 27311.2.1.2 Bioisosteres of the Conserved 2OG C5-Carboxylic Acid-Binding Motif 27311.2.2 Histone Substrate-Competitive Inhibitors 27511.2.2.1 Small-Molecule Inhibitors 27611.2.2.2 Peptide Inhibitors 27611.2.3 Allosteric Inhibitors 27611.2.4 Inhibitors Targeting KDM Subfamilies 27711.2.4.1 KDM4 Subfamily-Targeted Inhibitors 27711.2.4.2 KDM4/5 Subfamily-Targeted Inhibitors 27911.2.4.3 KDM5 Subfamily-Targeted Inhibitors 28011.2.4.4 KDM6 Subfamily-Targeted Inhibitors 28111.2.4.5 KDM2/7- and KDM3-Targeted Inhibitors 28211.2.4.6 Generic JmjC-KDM Inhibitors 28211.2.5 Selectivity and Potency of JmjC-KDM Inhibition in Cells 28311.3 KDM Inhibitors Targeting the Reader Domains 28411.3.1 Plant Homeodomain Fingers (PHD Fingers) 28411.3.2 Tudor Domains 28611.4 Conclusions and Future Perspectives 286Acknowledgments 287References 28712 Histone Acetyltransferases: Targets and Inhibitors 297Gianluca Sbardella12.1 Introduction 29712.2 Acetyltransferase Enzymes and Families 29812.3 The GNAT Superfamily 29912.3.1 KAT2A/GCN5 and KAT2B/PCAF 30112.3.2 KAT1/Hat1 30312.3.3 GCN5L1 30412.4 KAT3A/CBP and KAT3B/p300 Family 30412.5 MYST Family 30612.5.1 KAT5/Tip60 30612.5.2 KAT6A/MOZ, KAT6B/MORF, and KAT7/HBO1 30712.5.3 KAT8/MOF 30712.5.4 SAS2 and SAS3 30812.5.5 ESA1 30812.5.6 Other KATs 30812.6 KATs in Diseases 30912.7 KAT Modulators 31212.7.1 Bisubstrate Inhibitors 31312.7.2 Natural Products and Synthetic Analogues and Derivatives 31512.7.3 Synthetic Compounds 32112.7.4 Compounds Targeting Protein–Protein Interaction Domains 32812.8 Conclusion 333References 33413 Bromodomains: Promising Targets for Drug Discovery 347Mehrosh Pervaiz, PankajMishra, and Stefan Günther13.1 Introduction 34713.2 The Human Bromodomain Family 34813.2.1 Structural Features of the Human BRD Family 34813.2.1.1 The Kac Binding Site 34813.2.1.2 Druggability of the Human BRD Family 35013.2.2 Functions of Bromodomain-containing Proteins 35213.3 Bromodomains and Diseases 35313.3.1 The BET Family 35413.3.2 Non-BET Proteins 35613.4 Methods for the Identification of Bromodomain Inhibitors 35713.4.1 High-throughput Screening (HTS) 35713.4.2 Fragment-based Lead Discovery 35913.4.3 Structure-based Drug Design 35913.4.4 Virtual Screening 36213.4.4.1 Structure-based Virtual Screening 36213.4.4.2 Ligand-based Virtual Screening 36213.4.4.3 Pharmacophore Modeling 36313.4.4.4 Substructure and Similarity Search 36313.5 Current Bromodomain Inhibitors 36413.6 Multi-target Inhibitors 36513.6.1 Dual Kinase–Bromodomain Inhibitors 36513.6.2 Dual BET/HDAC Inhibitors 36913.7 Proteolysis Targeting Chimeras (PROTACs) 36913.8 Conclusions 371Acknowledgments 372References 37214 Lysine Reader Proteins 383Johannes Bacher, Dina Robaa, Chiara Luise,Wolfgang Sippl, and Manfred Jung14.1 Introduction 38314.2 The Royal Family of Epigenetic Reader Proteins 38514.2.1 The MBT Domain 38514.2.2 The PWWP Domain 39014.2.3 The Tudor Domain 39214.2.4 The Chromodomain 39514.3 The PHD Finger Family of Epigenetic Reader Proteins 40014.4 TheWD40 Repeat Domain Family 40214.5 Conclusion and Outlook 409Acknowledgment 409References 40915 DNA-modifying Enzymes 421Martin Roatsch, Dina Robaa,Michael Lübbert,Wolfgang Sippl, and Manfred Jung15.1 Introduction 42115.2 DNA Methylation 42215.3 Further Modifications of Cytosine Bases 42415.4 DNA Methyltransferases: Substrates and Structural Aspects 42615.5 Mechanism of Enzymatic DNA Methylation 43015.6 Physiological Role of DNA Methylation 43115.7 DNA Methylation in Disease 43215.8 DNMT Inhibitors 43315.8.1 Nucleoside-mimicking DNMT Inhibitors 43315.8.2 Non-nucleosidic DNMT Inhibitors 43615.9 Therapeutic Applications of DNMT Inhibitors 44115.10 Conclusion 442Acknowledgment 443References 44316 Parasite Epigenetic Targets 457Raymond J. Pierce and Jamal Khalife16.1 Introduction: The Global Problem of Parasitic Diseases and the Need for New Drugs 45716.2 Parasite Epigenetic Mechanisms 45816.2.1 DNA Methylation 45916.2.2 Histone Posttranslational Modifications 46016.2.3 Histone-modifying Enzymes in Parasites 46216.2.4 HMEs Validated as Therapeutic Targets 46216.2.5 Structure-based Approaches for Defining Therapeutic Targets 46416.3 Development of Epi-drugs for Parasitic Diseases 46516.3.1 Repurposing of Existing Epi-drugs 46616.3.2 Candidates from Phenotypic or High-throughput Screens 46716.3.3 Structure-based Development of Selective Inhibitors 46716.4 Conclusions 468Acknowledgments 469References 469Index 477

Wolfgang Sippl, PhD, holds the chair in Medicinal Chemistry at the Institute of Pharmacy at the Martin Luther University Halle-Wittenberg. Manfred Jung, PhD, is a full professor for Pharmaceutical Chemistry at the University of Freiburg and the co-chairman of the SFB research project "Medical Epigenetics".

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• Part I Introduction – Epigenetics 11 Epigenetics:Moving Forward 3Lucia Altucci1.1 Why This Enormously Increased Interest? 41.2 Looking Forward to New Avenues of Epigenetics 5Acknowledgments 7References 7Part II General Aspects/Methodologies 112 Structural Biology of Epigenetic Targets: Exploiting Complexity 13Martin Marek, Tajith B. Shaik, and Christophe Romier2.1 Introduction 132.2 DNA Methylases:The DNMT3A–DNMT3L–H3 and DNMT1–USP7 Complexes 142.3 Histone Arginine Methyltransferases:The PRMT5–MEP50 Complex 162.4 Histone Lysine Methyltransferases:The MLL3–RBBP5–ASH2L and the PRC2 Complexes 172.5 Histone Lysine Ubiquitinylases: The PRC1 Complex 212.6 Histone Lysine Deubiquitinylases: The SAGA Deubiquitination Module 222.7 Histone Acetyltransferases:The MSL1 and NUA4 Complexes 242.8 Histone Deacetylases: HDAC1–MTA1 and HDAC3–SMRT Complexes and HDAC6 262.9 Histone Variants and Histone Chaperones: A Complex and Modular Interplay 282.10 ATP-Dependent Remodelers: CHD1, ISWI, SNF2, and the SNF2-Nucleosome Complex 312.11 Epigenetic Readers: Histone Crotonylation Readers and the 53BP1-Nucleosome (H2AK15Ub–H4K20me2) Complex 352.12 Conclusions 37Acknowledgments 38References 383 Computer-based Lead Identification for Epigenetic Targets 45Chiara Luise, Tino Heimburg, Berin Karaman, Dina Robaa, andWolfgang Sippl3.1 Introduction 453.2 Computer-based Methods in Drug Discovery 463.2.1 Pharmacophore-based Methods 463.2.2 QSAR 473.2.3 Docking 473.2.4 Virtual Screening 483.2.5 Binding Free Energy Calculation 493.3 Histone Deacetylases 493.3.1 Zinc-Dependent HDACs 493.3.2 Sirtuins 543.4 Histone Methyltransferases 583.5 Histone Demethylases 613.5.1 LSD1 (KDM1A) 623.5.2 Jumonji Histone Demethylases 643.6 Summary 66Acknowledgments 66References 674 Mass Spectrometry and Chemical Biology in Epigenetics Drug Discovery 79Christian Feller, DavidWeigt, and Carsten Hopf4.1 Introduction: Mass Spectrometry Technology Used in Epigenetic Drug Discovery 794.1.1 Mass SpectrometryWorkflows for the Analysis of Proteins 804.1.2 Mass Spectrometry Imaging 834.2 Target Identification and Selectivity Profiling: Chemoproteomics 854.2.1 Histone Deacetylase and Acetyltransferase Chemoproteomics 874.2.2 Bromodomain Chemoproteomics 884.2.3 Demethylase Chemoproteomics 884.2.4 Methyltransferase Chemoproteomics 894.3 Characterization of Epigenetic Drug Target Complexes and Reader Complexes Contributing to Drug’s Mode of Action 894.3.1 Immunoaffinity Purification of Native Protein Complexes 894.3.2 Immunoaffinity Purification with Antibodies against Epitope Tags 904.3.3 Affinity Enrichment Using Histone Tail Peptides as Bait 914.4 Elucidation of a Drug’s Mode of Action: Analysis of Histone Posttranslational Modifications by MS-Based Proteomics 914.4.1 Histone Modification MS Workflows 924.4.2 Application of Histone MS Workflows to Characterize Epigenetic Drugs 954.5 Challenges and New Trends 974.5.1 Challenges and Trends in MS Analysis of Histone PTMs 974.5.2 High-Throughput Mass Spectrometry-Based Compound Profiling in Epigenetic Drug Discovery 984.5.3 Mass Spectrometry Imaging of Drug Action 98Acknowledgments 99References 995 PeptideMicroarrays for Epigenetic Targets 107Alexandra Schutkowski, Diana Kalbas, Ulf Reimer, andMike Schutkowski5.1 Introduction 1075.2 Applications of Peptide Microarrays for Epigenetic Targets 1105.2.1 Profiling of Substrate Specificities of Histone CodeWriters 1105.2.2 Profiling of Substrate Specificities of Histone Code Erasers 1145.2.3 Profiling of Binding Specificities of PTM-specific Antibodies and Histone Code Readers 1175.2.3.1 Profiling of Specificities of PTM-specific Antibodies 1185.2.3.2 Profiling of Binding Specificities of Histone Code Readers 1195.2.4 Peptide Microarray-based Identification of Upstream Kinases and Phosphorylation Sites for Epigenetic Targets 1215.3 Conclusion and Outlook 124Acknowledgment 124References 1246 Chemical Probes 133Amy Donner, Heather King, Paul E. Brennan, MosesMoustakim, andWilliam J. Zuercher6.1 Chemical Probes Are Privileged Reagents for Biological Research 1336.1.1 Best Practices for the Generation and Selection of Chemical Probes 1346.1.2 Best Practices for Application of Chemical Probes 1366.1.3 Cellular Target Engagement 1376.1.3.1 Fluorescence Recovery after Photobleaching (FRAP) 1386.1.3.2 Affinity Bead-Based Proteomics 1386.1.3.3 Cellular Thermal Shift Assay (CETSA) 1396.1.3.4 Bioluminescence Resonance Energy Transfer 1396.2 Epigenetic Chemical Probes 1416.2.1 Histone Acetylation and Bromodomain Chemical Probes 1416.2.1.1 CBP/p300 Bromodomain Chemical Probes 1446.2.1.2 Future Applications of Bromodomain Chemical Probes 1476.3 Summary 147References 148Part III Epigenetic Target Classes 1537 Inhibitors of the Zinc-Dependent Histone Deacetylases 155Helle M. E. Kristensen, Andreas S. Madsen, and Christian A. Olsen7.1 Introduction: Histone Deacetylases 1557.2 Histone Deacetylase Inhibitors 1587.2.1 Types of Inhibitors 1587.2.2 HDAC Inhibitors in Clinical Use and Development 1607.3 Targeting of HDAC Subclasses 1697.3.1 Class I Inhibitors 1697.3.1.1 HDAC1–3 Inhibitors 1707.3.1.2 HDAC Inhibitors Targeting HDAC8 1737.3.2 Class IIa Inhibitors 1747.3.3 Class IIb 1767.4 Perspectives 177References 1798 Sirtuins as Drug Targets 185Clemens Zwergel, Dante Rotili, Sergio Valente, and Antonello Mai8.1 Introduction 1858.2 Biological Functions of Sirtuins in Physiology and Pathology 1858.3 SIRT Modulators 1888.3.1 SIRT Inhibitors 1888.3.1.1 Small Molecules 1888.3.1.2 Peptides and Pseudopeptides 1918.3.2 SIRT Activators 1918.4 Summary and Conclusions 192References 1939 Selective Small-Molecule Inhibitors of Protein Methyltransferases 201H. Ümit Kaniskan and Jian Jin9.1 Introduction 2019.2 Protein Methylation 2019.3 Lysine Methyltransferases (PKMTs) 2029.4 Inhibitors of PKMTs 2029.4.1 Inhibitors of H3K9 Methyltransferases 2029.4.2 Inhibitors of H3K27 Methyltransferases 2049.4.3 Inhibitors of H3K4 and H3K36 Methyltransferases 2069.4.4 Inhibitors of H4K20 Methyltransferases 2089.4.5 Inhibitors of H3K79 Methyltransferases 2109.5 Protein Arginine Methyltransferases (PRMTs) 2119.5.1 Inhibitors of PRMT1 2119.5.2 Inhibitors of PRMT3 2129.5.3 Inhibitors of CARM1 2139.5.4 Inhibitors of PRMT5 2149.5.5 Inhibitors of PRMT6 2149.6 Concluding Remarks 215References 21510 LSD (Lysine-Specific Demethylase): A Decade-Long Trip from Discovery to Clinical Trials 221Adam Lee, M. Teresa Borrello, and A. Ganesan10.1 Introduction 22110.2 LSDs: Discovery and Mechanistic Features 22310.3 LSD Substrates 22510.4 LSD Function and Dysfunction 22910.5 LSD Inhibitors 23210.5.1 Irreversible Small Molecule LSD Inhibitors from MAO Inhibitors 23310.5.2 Reversible Small Molecule LSD Inhibitors 24110.5.3 Synthetic Macromolecular LSD Inhibitors 24810.6 Summary 251References 25311 JmjC-domain-Containing Histone Demethylases 263Christoffer Højrup, Oliver D. Coleman, John-Paul Bukowski, Rasmus P. Clausen, and Akane Kawamura11.1 Introduction 26311.1.1 The LSD and JmjC Histone Lysine Demethylases 26311.1.2 Histone Lysine Methylation and the JmjC-KDMs 26511.1.3 The JmjC-KDMs in Development and Disease 26611.2 KDM Inhibitor Development Targeting the JmjC Domain 27211.2.1 2-Oxoglutarate Cofactor Mimicking Inhibitors 27311.2.1.1 Emulation of the Chelating α-Keto AcidMoiety in 2OG 27311.2.1.2 Bioisosteres of the Conserved 2OG C5-Carboxylic Acid-Binding Motif 27311.2.2 Histone Substrate-Competitive Inhibitors 27511.2.2.1 Small-Molecule Inhibitors 27611.2.2.2 Peptide Inhibitors 27611.2.3 Allosteric Inhibitors 27611.2.4 Inhibitors Targeting KDM Subfamilies 27711.2.4.1 KDM4 Subfamily-Targeted Inhibitors 27711.2.4.2 KDM4/5 Subfamily-Targeted Inhibitors 27911.2.4.3 KDM5 Subfamily-Targeted Inhibitors 28011.2.4.4 KDM6 Subfamily-Targeted Inhibitors 28111.2.4.5 KDM2/7- and KDM3-Targeted Inhibitors 28211.2.4.6 Generic JmjC-KDM Inhibitors 28211.2.5 Selectivity and Potency of JmjC-KDM Inhibition in Cells 28311.3 KDM Inhibitors Targeting the Reader Domains 28411.3.1 Plant Homeodomain Fingers (PHD Fingers) 28411.3.2 Tudor Domains 28611.4 Conclusions and Future Perspectives 286Acknowledgments 287References 28712 Histone Acetyltransferases: Targets and Inhibitors 297Gianluca Sbardella12.1 Introduction 29712.2 Acetyltransferase Enzymes and Families 29812.3 The GNAT Superfamily 29912.3.1 KAT2A/GCN5 and KAT2B/PCAF 30112.3.2 KAT1/Hat1 30312.3.3 GCN5L1 30412.4 KAT3A/CBP and KAT3B/p300 Family 30412.5 MYST Family 30612.5.1 KAT5/Tip60 30612.5.2 KAT6A/MOZ, KAT6B/MORF, and KAT7/HBO1 30712.5.3 KAT8/MOF 30712.5.4 SAS2 and SAS3 30812.5.5 ESA1 30812.5.6 Other KATs 30812.6 KATs in Diseases 30912.7 KAT Modulators 31212.7.1 Bisubstrate Inhibitors 31312.7.2 Natural Products and Synthetic Analogues and Derivatives 31512.7.3 Synthetic Compounds 32112.7.4 Compounds Targeting Protein–Protein Interaction Domains 32812.8 Conclusion 333References 33413 Bromodomains: Promising Targets for Drug Discovery 347Mehrosh Pervaiz, PankajMishra, and Stefan Günther13.1 Introduction 34713.2 The Human Bromodomain Family 34813.2.1 Structural Features of the Human BRD Family 34813.2.1.1 The Kac Binding Site 34813.2.1.2 Druggability of the Human BRD Family 35013.2.2 Functions of Bromodomain-containing Proteins 35213.3 Bromodomains and Diseases 35313.3.1 The BET Family 35413.3.2 Non-BET Proteins 35613.4 Methods for the Identification of Bromodomain Inhibitors 35713.4.1 High-throughput Screening (HTS) 35713.4.2 Fragment-based Lead Discovery 35913.4.3 Structure-based Drug Design 35913.4.4 Virtual Screening 36213.4.4.1 Structure-based Virtual Screening 36213.4.4.2 Ligand-based Virtual Screening 36213.4.4.3 Pharmacophore Modeling 36313.4.4.4 Substructure and Similarity Search 36313.5 Current Bromodomain Inhibitors 36413.6 Multi-target Inhibitors 36513.6.1 Dual Kinase–Bromodomain Inhibitors 36513.6.2 Dual BET/HDAC Inhibitors 36913.7 Proteolysis Targeting Chimeras (PROTACs) 36913.8 Conclusions 371Acknowledgments 372References 37214 Lysine Reader Proteins 383Johannes Bacher, Dina Robaa, Chiara Luise,Wolfgang Sippl, and Manfred Jung14.1 Introduction 38314.2 The Royal Family of Epigenetic Reader Proteins 38514.2.1 The MBT Domain 38514.2.2 The PWWP Domain 39014.2.3 The Tudor Domain 39214.2.4 The Chromodomain 39514.3 The PHD Finger Family of Epigenetic Reader Proteins 40014.4 TheWD40 Repeat Domain Family 40214.5 Conclusion and Outlook 409Acknowledgment 409References 40915 DNA-modifying Enzymes 421Martin Roatsch, Dina Robaa,Michael Lübbert,Wolfgang Sippl, and Manfred Jung15.1 Introduction 42115.2 DNA Methylation 42215.3 Further Modifications of Cytosine Bases 42415.4 DNA Methyltransferases: Substrates and Structural Aspects 42615.5 Mechanism of Enzymatic DNA Methylation 43015.6 Physiological Role of DNA Methylation 43115.7 DNA Methylation in Disease 43215.8 DNMT Inhibitors 43315.8.1 Nucleoside-mimicking DNMT Inhibitors 43315.8.2 Non-nucleosidic DNMT Inhibitors 43615.9 Therapeutic Applications of DNMT Inhibitors 44115.10 Conclusion 442Acknowledgment 443References 44316 Parasite Epigenetic Targets 457Raymond J. Pierce and Jamal Khalife16.1 Introduction: The Global Problem of Parasitic Diseases and the Need for New Drugs 45716.2 Parasite Epigenetic Mechanisms 45816.2.1 DNA Methylation 45916.2.2 Histone Posttranslational Modifications 46016.2.3 Histone-modifying Enzymes in Parasites 46216.2.4 HMEs Validated as Therapeutic Targets 46216.2.5 Structure-based Approaches for Defining Therapeutic Targets 46416.3 Development of Epi-drugs for Parasitic Diseases 46516.3.1 Repurposing of Existing Epi-drugs 46616.3.2 Candidates from Phenotypic or High-throughput Screens 46716.3.3 Structure-based Development of Selective Inhibitors 46716.4 Conclusions 468Acknowledgments 469References 469Index 477

Wolfgang Sippl, PhD, holds the chair in Medicinal Chemistry at the Institute of Pharmacy at the Martin Luther University Halle-Wittenberg. Manfred Jung, PhD, is a full professor for Pharmaceutical Chemistry at the University of Freiburg and the co-chairman of the SFB research project "Medical Epigenetics".

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• Part I Introduction – Epigenetics 11 Epigenetics:Moving Forward 3Lucia Altucci1.1 Why This Enormously Increased Interest? 41.2 Looking Forward to New Avenues of Epigenetics 5Acknowledgments 7References 7Part II General Aspects/Methodologies 112 Structural Biology of Epigenetic Targets: Exploiting Complexity 13Martin Marek, Tajith B. Shaik, and Christophe Romier2.1 Introduction 132.2 DNA Methylases:The DNMT3A–DNMT3L–H3 and DNMT1–USP7 Complexes 142.3 Histone Arginine Methyltransferases:The PRMT5–MEP50 Complex 162.4 Histone Lysine Methyltransferases:The MLL3–RBBP5–ASH2L and the PRC2 Complexes 172.5 Histone Lysine Ubiquitinylases: The PRC1 Complex 212.6 Histone Lysine Deubiquitinylases: The SAGA Deubiquitination Module 222.7 Histone Acetyltransferases:The MSL1 and NUA4 Complexes 242.8 Histone Deacetylases: HDAC1–MTA1 and HDAC3–SMRT Complexes and HDAC6 262.9 Histone Variants and Histone Chaperones: A Complex and Modular Interplay 282.10 ATP-Dependent Remodelers: CHD1, ISWI, SNF2, and the SNF2-Nucleosome Complex 312.11 Epigenetic Readers: Histone Crotonylation Readers and the 53BP1-Nucleosome (H2AK15Ub–H4K20me2) Complex 352.12 Conclusions 37Acknowledgments 38References 383 Computer-based Lead Identification for Epigenetic Targets 45Chiara Luise, Tino Heimburg, Berin Karaman, Dina Robaa, andWolfgang Sippl3.1 Introduction 453.2 Computer-based Methods in Drug Discovery 463.2.1 Pharmacophore-based Methods 463.2.2 QSAR 473.2.3 Docking 473.2.4 Virtual Screening 483.2.5 Binding Free Energy Calculation 493.3 Histone Deacetylases 493.3.1 Zinc-Dependent HDACs 493.3.2 Sirtuins 543.4 Histone Methyltransferases 583.5 Histone Demethylases 613.5.1 LSD1 (KDM1A) 623.5.2 Jumonji Histone Demethylases 643.6 Summary 66Acknowledgments 66References 674 Mass Spectrometry and Chemical Biology in Epigenetics Drug Discovery 79Christian Feller, DavidWeigt, and Carsten Hopf4.1 Introduction: Mass Spectrometry Technology Used in Epigenetic Drug Discovery 794.1.1 Mass SpectrometryWorkflows for the Analysis of Proteins 804.1.2 Mass Spectrometry Imaging 834.2 Target Identification and Selectivity Profiling: Chemoproteomics 854.2.1 Histone Deacetylase and Acetyltransferase Chemoproteomics 874.2.2 Bromodomain Chemoproteomics 884.2.3 Demethylase Chemoproteomics 884.2.4 Methyltransferase Chemoproteomics 894.3 Characterization of Epigenetic Drug Target Complexes and Reader Complexes Contributing to Drug’s Mode of Action 894.3.1 Immunoaffinity Purification of Native Protein Complexes 894.3.2 Immunoaffinity Purification with Antibodies against Epitope Tags 904.3.3 Affinity Enrichment Using Histone Tail Peptides as Bait 914.4 Elucidation of a Drug’s Mode of Action: Analysis of Histone Posttranslational Modifications by MS-Based Proteomics 914.4.1 Histone Modification MS Workflows 924.4.2 Application of Histone MS Workflows to Characterize Epigenetic Drugs 954.5 Challenges and New Trends 974.5.1 Challenges and Trends in MS Analysis of Histone PTMs 974.5.2 High-Throughput Mass Spectrometry-Based Compound Profiling in Epigenetic Drug Discovery 984.5.3 Mass Spectrometry Imaging of Drug Action 98Acknowledgments 99References 995 PeptideMicroarrays for Epigenetic Targets 107Alexandra Schutkowski, Diana Kalbas, Ulf Reimer, andMike Schutkowski5.1 Introduction 1075.2 Applications of Peptide Microarrays for Epigenetic Targets 1105.2.1 Profiling of Substrate Specificities of Histone CodeWriters 1105.2.2 Profiling of Substrate Specificities of Histone Code Erasers 1145.2.3 Profiling of Binding Specificities of PTM-specific Antibodies and Histone Code Readers 1175.2.3.1 Profiling of Specificities of PTM-specific Antibodies 1185.2.3.2 Profiling of Binding Specificities of Histone Code Readers 1195.2.4 Peptide Microarray-based Identification of Upstream Kinases and Phosphorylation Sites for Epigenetic Targets 1215.3 Conclusion and Outlook 124Acknowledgment 124References 1246 Chemical Probes 133Amy Donner, Heather King, Paul E. Brennan, MosesMoustakim, andWilliam J. Zuercher6.1 Chemical Probes Are Privileged Reagents for Biological Research 1336.1.1 Best Practices for the Generation and Selection of Chemical Probes 1346.1.2 Best Practices for Application of Chemical Probes 1366.1.3 Cellular Target Engagement 1376.1.3.1 Fluorescence Recovery after Photobleaching (FRAP) 1386.1.3.2 Affinity Bead-Based Proteomics 1386.1.3.3 Cellular Thermal Shift Assay (CETSA) 1396.1.3.4 Bioluminescence Resonance Energy Transfer 1396.2 Epigenetic Chemical Probes 1416.2.1 Histone Acetylation and Bromodomain Chemical Probes 1416.2.1.1 CBP/p300 Bromodomain Chemical Probes 1446.2.1.2 Future Applications of Bromodomain Chemical Probes 1476.3 Summary 147References 148Part III Epigenetic Target Classes 1537 Inhibitors of the Zinc-Dependent Histone Deacetylases 155Helle M. E. Kristensen, Andreas S. Madsen, and Christian A. Olsen7.1 Introduction: Histone Deacetylases 1557.2 Histone Deacetylase Inhibitors 1587.2.1 Types of Inhibitors 1587.2.2 HDAC Inhibitors in Clinical Use and Development 1607.3 Targeting of HDAC Subclasses 1697.3.1 Class I Inhibitors 1697.3.1.1 HDAC1–3 Inhibitors 1707.3.1.2 HDAC Inhibitors Targeting HDAC8 1737.3.2 Class IIa Inhibitors 1747.3.3 Class IIb 1767.4 Perspectives 177References 1798 Sirtuins as Drug Targets 185Clemens Zwergel, Dante Rotili, Sergio Valente, and Antonello Mai8.1 Introduction 1858.2 Biological Functions of Sirtuins in Physiology and Pathology 1858.3 SIRT Modulators 1888.3.1 SIRT Inhibitors 1888.3.1.1 Small Molecules 1888.3.1.2 Peptides and Pseudopeptides 1918.3.2 SIRT Activators 1918.4 Summary and Conclusions 192References 1939 Selective Small-Molecule Inhibitors of Protein Methyltransferases 201H. Ümit Kaniskan and Jian Jin9.1 Introduction 2019.2 Protein Methylation 2019.3 Lysine Methyltransferases (PKMTs) 2029.4 Inhibitors of PKMTs 2029.4.1 Inhibitors of H3K9 Methyltransferases 2029.4.2 Inhibitors of H3K27 Methyltransferases 2049.4.3 Inhibitors of H3K4 and H3K36 Methyltransferases 2069.4.4 Inhibitors of H4K20 Methyltransferases 2089.4.5 Inhibitors of H3K79 Methyltransferases 2109.5 Protein Arginine Methyltransferases (PRMTs) 2119.5.1 Inhibitors of PRMT1 2119.5.2 Inhibitors of PRMT3 2129.5.3 Inhibitors of CARM1 2139.5.4 Inhibitors of PRMT5 2149.5.5 Inhibitors of PRMT6 2149.6 Concluding Remarks 215References 21510 LSD (Lysine-Specific Demethylase): A Decade-Long Trip from Discovery to Clinical Trials 221Adam Lee, M. Teresa Borrello, and A. Ganesan10.1 Introduction 22110.2 LSDs: Discovery and Mechanistic Features 22310.3 LSD Substrates 22510.4 LSD Function and Dysfunction 22910.5 LSD Inhibitors 23210.5.1 Irreversible Small Molecule LSD Inhibitors from MAO Inhibitors 23310.5.2 Reversible Small Molecule LSD Inhibitors 24110.5.3 Synthetic Macromolecular LSD Inhibitors 24810.6 Summary 251References 25311 JmjC-domain-Containing Histone Demethylases 263Christoffer Højrup, Oliver D. Coleman, John-Paul Bukowski, Rasmus P. Clausen, and Akane Kawamura11.1 Introduction 26311.1.1 The LSD and JmjC Histone Lysine Demethylases 26311.1.2 Histone Lysine Methylation and the JmjC-KDMs 26511.1.3 The JmjC-KDMs in Development and Disease 26611.2 KDM Inhibitor Development Targeting the JmjC Domain 27211.2.1 2-Oxoglutarate Cofactor Mimicking Inhibitors 27311.2.1.1 Emulation of the Chelating α-Keto AcidMoiety in 2OG 27311.2.1.2 Bioisosteres of the Conserved 2OG C5-Carboxylic Acid-Binding Motif 27311.2.2 Histone Substrate-Competitive Inhibitors 27511.2.2.1 Small-Molecule Inhibitors 27611.2.2.2 Peptide Inhibitors 27611.2.3 Allosteric Inhibitors 27611.2.4 Inhibitors Targeting KDM Subfamilies 27711.2.4.1 KDM4 Subfamily-Targeted Inhibitors 27711.2.4.2 KDM4/5 Subfamily-Targeted Inhibitors 27911.2.4.3 KDM5 Subfamily-Targeted Inhibitors 28011.2.4.4 KDM6 Subfamily-Targeted Inhibitors 28111.2.4.5 KDM2/7- and KDM3-Targeted Inhibitors 28211.2.4.6 Generic JmjC-KDM Inhibitors 28211.2.5 Selectivity and Potency of JmjC-KDM Inhibition in Cells 28311.3 KDM Inhibitors Targeting the Reader Domains 28411.3.1 Plant Homeodomain Fingers (PHD Fingers) 28411.3.2 Tudor Domains 28611.4 Conclusions and Future Perspectives 286Acknowledgments 287References 28712 Histone Acetyltransferases: Targets and Inhibitors 297Gianluca Sbardella12.1 Introduction 29712.2 Acetyltransferase Enzymes and Families 29812.3 The GNAT Superfamily 29912.3.1 KAT2A/GCN5 and KAT2B/PCAF 30112.3.2 KAT1/Hat1 30312.3.3 GCN5L1 30412.4 KAT3A/CBP and KAT3B/p300 Family 30412.5 MYST Family 30612.5.1 KAT5/Tip60 30612.5.2 KAT6A/MOZ, KAT6B/MORF, and KAT7/HBO1 30712.5.3 KAT8/MOF 30712.5.4 SAS2 and SAS3 30812.5.5 ESA1 30812.5.6 Other KATs 30812.6 KATs in Diseases 30912.7 KAT Modulators 31212.7.1 Bisubstrate Inhibitors 31312.7.2 Natural Products and Synthetic Analogues and Derivatives 31512.7.3 Synthetic Compounds 32112.7.4 Compounds Targeting Protein–Protein Interaction Domains 32812.8 Conclusion 333References 33413 Bromodomains: Promising Targets for Drug Discovery 347Mehrosh Pervaiz, PankajMishra, and Stefan Günther13.1 Introduction 34713.2 The Human Bromodomain Family 34813.2.1 Structural Features of the Human BRD Family 34813.2.1.1 The Kac Binding Site 34813.2.1.2 Druggability of the Human BRD Family 35013.2.2 Functions of Bromodomain-containing Proteins 35213.3 Bromodomains and Diseases 35313.3.1 The BET Family 35413.3.2 Non-BET Proteins 35613.4 Methods for the Identification of Bromodomain Inhibitors 35713.4.1 High-throughput Screening (HTS) 35713.4.2 Fragment-based Lead Discovery 35913.4.3 Structure-based Drug Design 35913.4.4 Virtual Screening 36213.4.4.1 Structure-based Virtual Screening 36213.4.4.2 Ligand-based Virtual Screening 36213.4.4.3 Pharmacophore Modeling 36313.4.4.4 Substructure and Similarity Search 36313.5 Current Bromodomain Inhibitors 36413.6 Multi-target Inhibitors 36513.6.1 Dual Kinase–Bromodomain Inhibitors 36513.6.2 Dual BET/HDAC Inhibitors 36913.7 Proteolysis Targeting Chimeras (PROTACs) 36913.8 Conclusions 371Acknowledgments 372References 37214 Lysine Reader Proteins 383Johannes Bacher, Dina Robaa, Chiara Luise,Wolfgang Sippl, and Manfred Jung14.1 Introduction 38314.2 The Royal Family of Epigenetic Reader Proteins 38514.2.1 The MBT Domain 38514.2.2 The PWWP Domain 39014.2.3 The Tudor Domain 39214.2.4 The Chromodomain 39514.3 The PHD Finger Family of Epigenetic Reader Proteins 40014.4 TheWD40 Repeat Domain Family 40214.5 Conclusion and Outlook 409Acknowledgment 409References 40915 DNA-modifying Enzymes 421Martin Roatsch, Dina Robaa,Michael Lübbert,Wolfgang Sippl, and Manfred Jung15.1 Introduction 42115.2 DNA Methylation 42215.3 Further Modifications of Cytosine Bases 42415.4 DNA Methyltransferases: Substrates and Structural Aspects 42615.5 Mechanism of Enzymatic DNA Methylation 43015.6 Physiological Role of DNA Methylation 43115.7 DNA Methylation in Disease 43215.8 DNMT Inhibitors 43315.8.1 Nucleoside-mimicking DNMT Inhibitors 43315.8.2 Non-nucleosidic DNMT Inhibitors 43615.9 Therapeutic Applications of DNMT Inhibitors 44115.10 Conclusion 442Acknowledgment 443References 44316 Parasite Epigenetic Targets 457Raymond J. Pierce and Jamal Khalife16.1 Introduction: The Global Problem of Parasitic Diseases and the Need for New Drugs 45716.2 Parasite Epigenetic Mechanisms 45816.2.1 DNA Methylation 45916.2.2 Histone Posttranslational Modifications 46016.2.3 Histone-modifying Enzymes in Parasites 46216.2.4 HMEs Validated as Therapeutic Targets 46216.2.5 Structure-based Approaches for Defining Therapeutic Targets 46416.3 Development of Epi-drugs for Parasitic Diseases 46516.3.1 Repurposing of Existing Epi-drugs 46616.3.2 Candidates from Phenotypic or High-throughput Screens 46716.3.3 Structure-based Development of Selective Inhibitors 46716.4 Conclusions 468Acknowledgments 469References 469Index 477