Epigenetic drug discovery /

Bibliographic Details
Other Authors:	Sippl, Wolfgang (Editor), Jung, Manfred (Editor)
Format:	eBook
Language:	English
Published:	Weinheim, Germany : Wiley-VCH, 2019.
Series:	Methods and principles in medicinal chemistry ; volume 74.
Subjects:	Pharmacogenomics. Electronic books.
Online Access:	Connect to the full text of this electronic book

Table of Contents:

Part I Introduction
Epigenetics 1 1 Epigenetics:Moving Forward 3 Lucia Altucci 1.1 Why This Enormously Increased Interest? 4 1.2 Looking Forward to New Avenues of Epigenetics 5 Acknowledgments 7 References 7 Part II General Aspects/Methodologies 11 2 Structural Biology of Epigenetic Targets: Exploiting Complexity 13 Martin Marek, Tajith B. Shaik, and Christophe Romier 2.1 Introduction 13 2.2 DNA Methylases:The DNMT3A-DNMT3L-H3 and DNMT1-USP7 Complexes 14 2.3 Histone Arginine Methyltransferases:The PRMT5-MEP50 Complex 16 2.4 Histone Lysine Methyltransferases:The MLL3-RBBP5-ASH2L and the PRC2 Complexes 17 2.5 Histone Lysine Ubiquitinylases: The PRC1 Complex 21 2.6 Histone Lysine Deubiquitinylases: The SAGA Deubiquitination Module 22 2.7 Histone Acetyltransferases:The MSL1 and NUA4 Complexes 24 2.8 Histone Deacetylases: HDAC1-MTA1 and HDAC3-SMRT Complexes and HDAC6 26 2.9 Histone Variants and Histone Chaperones: A Complex and Modular Interplay 28 2.10 ATP-Dependent Remodelers: CHD1, ISWI, SNF2, and the SNF2-Nucleosome Complex 31 2.11 Epigenetic Readers: Histone Crotonylation Readers and the 53BP1-Nucleosome (H2AK15Ub-H4K20me2) Complex 35 2.12 Conclusions 37 Acknowledgments 38 References 38 3 Computer-based Lead Identification for Epigenetic Targets 45 Chiara Luise, Tino Heimburg, Berin Karaman, Dina Robaa, andWolfgang Sippl 3.1 Introduction 45 3.2 Computer-based Methods in Drug Discovery 46 3.2.1 Pharmacophore-based Methods 46 3.2.2 QSAR 47 3.2.3 Docking 47 3.2.4 Virtual Screening 48 3.2.5 Binding Free Energy Calculation 49 3.3 Histone Deacetylases 49 3.3.1 Zinc-Dependent HDACs 49 3.3.2 Sirtuins 54 3.4 Histone Methyltransferases 58 3.5 Histone Demethylases 61 3.5.1 LSD1 (KDM1A) 62 3.5.2 Jumonji Histone Demethylases 64 3.6 Summary 66 Acknowledgments 66 References 67 4 Mass Spectrometry and Chemical Biology in Epigenetics Drug Discovery 79 Christian Feller, DavidWeigt, and Carsten Hopf 4.1 Introduction: Mass Spectrometry Technology Used in Epigenetic Drug Discovery 79 4.1.1 Mass SpectrometryWorkflows for the Analysis of Proteins 80 4.1.2 Mass Spectrometry Imaging 83 4.2 Target Identification and Selectivity Profiling: Chemoproteomics 85 4.2.1 Histone Deacetylase and Acetyltransferase Chemoproteomics 87 4.2.2 Bromodomain Chemoproteomics 88 4.2.3 Demethylase Chemoproteomics 88 4.2.4 Methyltransferase Chemoproteomics 89 4.3 Characterization of Epigenetic Drug Target Complexes and Reader Complexes Contributing to Drug's Mode of Action 89 4.3.1 Immunoaffinity Purification of Native Protein Complexes 89 4.3.2 Immunoaffinity Purification with Antibodies against Epitope Tags 90 4.3.3 Affinity Enrichment Using Histone Tail Peptides as Bait 91 4.4 Elucidation of a Drug's Mode of Action: Analysis of Histone Posttranslational Modifications by MS-Based Proteomics 91 4.4.1 Histone Modification MS Workflows 92 4.4.2 Application of Histone MS Workflows to Characterize Epigenetic Drugs 95 4.5 Challenges and New Trends 97 4.5.1 Challenges and Trends in MS Analysis of Histone PTMs 97 4.5.2 High-Throughput Mass Spectrometry-Based Compound Profiling in Epigenetic Drug Discovery 98 4.5.3 Mass Spectrometry Imaging of Drug Action 98 Acknowledgments 99 References 99 5 PeptideMicroarrays for Epigenetic Targets 107 Alexandra Schutkowski, Diana Kalbas, Ulf Reimer, andMike Schutkowski 5.1 Introduction 107 5.2 Applications of Peptide Microarrays for Epigenetic Targets 110 5.2.1 Profiling of Substrate Specificities of Histone CodeWriters 110 5.2.2 Profiling of Substrate Specificities of Histone Code Erasers 114 5.2.3 Profiling of Binding Specificities of PTM-specific Antibodies and Histone Code Readers 117 5.2.3.1 Profiling of Specificities of PTM-specific Antibodies 118 5.2.3.2 Profiling of Binding Specificities of Histone Code Readers 119 5.2.4 Peptide Microarray-based Identification of Upstream Kinases and Phosphorylation Sites for Epigenetic Targets 121 5.3 Conclusion and Outlook 124 Acknowledgment 124 References 124 6 Chemical Probes 133 Amy Donner, Heather King, Paul E. Brennan, MosesMoustakim, andWilliam J. Zuercher 6.1 Chemical Probes Are Privileged Reagents for Biological Research 133 6.1.1 Best Practices for the Generation and Selection of Chemical Probes 134 6.1.2 Best Practices for Application of Chemical Probes 136 6.1.3 Cellular Target Engagement 137 6.1.3.1 Fluorescence Recovery after Photobleaching (FRAP) 138 6.1.3.2 Affinity Bead-Based Proteomics 138 6.1.3.3 Cellular Thermal Shift Assay (CETSA) 139 6.1.3.4 Bioluminescence Resonance Energy Transfer 139 6.2 Epigenetic Chemical Probes 141 6.2.1 Histone Acetylation and Bromodomain Chemical Probes 141 6.2.1.1 CBP/p300 Bromodomain Chemical Probes 144 6.2.1.2 Future Applications of Bromodomain Chemical Probes 147 6.3 Summary 147 References 148 Part III Epigenetic Target Classes 153 7 Inhibitors of the Zinc-Dependent Histone Deacetylases 155 Helle M. E. Kristensen, Andreas S. Madsen, and Christian A. Olsen 7.1 Introduction: Histone Deacetylases 155 7.2 Histone Deacetylase Inhibitors 158 7.2.1 Types of Inhibitors 158 7.2.2 HDAC Inhibitors in Clinical Use and Development 160 7.3 Targeting of HDAC Subclasses 169 7.3.1 Class I Inhibitors 169 7.3.1.1 HDAC1-3 Inhibitors 170 7.3.1.2 HDAC Inhibitors Targeting HDAC8 173 7.3.2 Class IIa Inhibitors 174 7.3.3 Class IIb 176 7.4 Perspectives 177 References 179 8 Sirtuins as Drug Targets 185 Clemens Zwergel, Dante Rotili, Sergio Valente, and Antonello Mai 8.1 Introduction 185 8.2 Biological Functions of Sirtuins in Physiology and Pathology 185 8.3 SIRT Modulators 188 8.3.1 SIRT Inhibitors 188 8.3.1.1 Small Molecules 188 8.3.1.2 Peptides and Pseudopeptides 191 8.3.2 SIRT Activators 191 8.4 Summary and Conclusions 192 References 193 9 Selective Small-Molecule Inhibitors of Protein Methyltransferases 201 H. Ümit Kaniskan and Jian Jin 9.1 Introduction 201 9.2 Protein Methylation 201 9.3 Lysine Methyltransferases (PKMTs) 202 9.4 Inhibitors of PKMTs 202 9.4.1 Inhibitors of H3K9 Methyltransferases 202 9.4.2 Inhibitors of H3K27 Methyltransferases 204 9.4.3 Inhibitors of H3K4 and H3K36 Methyltransferases 206 9.4.4 Inhibitors of H4K20 Methyltransferases 208 9.4.5 Inhibitors of H3K79 Methyltransferases 210 9.5 Protein Arginine Methyltransferases (PRMTs) 211 9.5.1 Inhibitors of PRMT1 211 9.5.2 Inhibitors of PRMT3 212 9.5.3 Inhibitors of CARM1 213 9.5.4 Inhibitors of PRMT5 214 9.5.5 Inhibitors of PRMT6 214 9.6 Concluding Remarks 215 References 215 10 LSD (Lysine-Specific Demethylase): A Decade-Long Trip from Discovery to Clinical Trials 221 Adam Lee, M. Teresa Borrello, and A. Ganesan 10.1 Introduction 221 10.2 LSDs: Discovery and Mechanistic Features 223 10.3 LSD Substrates 225 10.4 LSD Function and Dysfunction 229 10.5 LSD Inhibitors 232 10.5.1 Irreversible Small Molecule LSD Inhibitors from MAO Inhibitors 233 10.5.2 Reversible Small M