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Epigenetic Drug Discovery

Methods & Principles in Medicinal Chemistry 1. Aufl.

von: Wolfgang Sippl, Manfred Jung, Raimund Mannhold, Helmut Buschmann, Jörg Holenz
162,99 €
Verlag:	Wiley-VCH
Format:	EPUB
Veröffentl.:	26.11.2018
ISBN/EAN:	9783527809264
Sprache:	englisch
Anzahl Seiten:	504

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Titelbeschreibung

This broad view of epigenetic approaches in drug discovery combines methods and strategies with individual targets, including new and largely unexplored ones such as sirtuins and methyl-lysine reader proteins. Presented in three parts - Introduction to Epigenetics, General Aspects and Methodologies, and Epigenetic Target Classes - it covers everything any drug researcher would need in order to know about targeting epigenetic mechanisms of disease. Epigenetic Drug Discovery is an important resource for medicinal chemists, pharmaceutical researchers, biochemists, molecular biologists, and molecular geneticists.

Inhaltsverzeichnis

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 Molecule LSD Inhibitors 241 10.5.3 Synthetic Macromolecular LSD Inhibitors 248 10.6 Summary 251 References 253 11 JmjC-domain-Containing Histone Demethylases 263 Christoffer Højrup, Oliver D. Coleman, John-Paul Bukowski, Rasmus P. Clausen, and Akane Kawamura 11.1 Introduction 263 11.1.1 The LSD and JmjC Histone Lysine Demethylases 263 11.1.2 Histone Lysine Methylation and the JmjC-KDMs 265 11.1.3 The JmjC-KDMs in Development and Disease 266 11.2 KDM Inhibitor Development Targeting the JmjC Domain 272 11.2.1 2-Oxoglutarate Cofactor Mimicking Inhibitors 273 11.2.1.1 Emulation of the Chelating α-Keto AcidMoiety in 2OG 273 11.2.1.2 Bioisosteres of the Conserved 2OG C5-Carboxylic Acid-Binding Motif 273 11.2.2 Histone Substrate-Competitive Inhibitors 275 11.2.2.1 Small-Molecule Inhibitors 276 11.2.2.2 Peptide Inhibitors 276 11.2.3 Allosteric Inhibitors 276 11.2.4 Inhibitors Targeting KDM Subfamilies 277 11.2.4.1 KDM4 Subfamily-Targeted Inhibitors 277 11.2.4.2 KDM4/5 Subfamily-Targeted Inhibitors 279 11.2.4.3 KDM5 Subfamily-Targeted Inhibitors 280 11.2.4.4 KDM6 Subfamily-Targeted Inhibitors 281 11.2.4.5 KDM2/7- and KDM3-Targeted Inhibitors 282 11.2.4.6 Generic JmjC-KDM Inhibitors 282 11.2.5 Selectivity and Potency of JmjC-KDM Inhibition in Cells 283 11.3 KDM Inhibitors Targeting the Reader Domains 284 11.3.1 Plant Homeodomain Fingers (PHD Fingers) 284 11.3.2 Tudor Domains 286 11.4 Conclusions and Future Perspectives 286 Acknowledgments 287 References 287 12 Histone Acetyltransferases: Targets and Inhibitors 297 Gianluca Sbardella 12.1 Introduction 297 12.2 Acetyltransferase Enzymes and Families 298 12.3 The GNAT Superfamily 299 12.3.1 KAT2A/GCN5 and KAT2B/PCAF 301 12.3.2 KAT1/Hat1 303 12.3.3 GCN5L1 304 12.4 KAT3A/CBP and KAT3B/p300 Family 304 12.5 MYST Family 306 12.5.1 KAT5/Tip60 306 12.5.2 KAT6A/MOZ, KAT6B/MORF, and KAT7/HBO1 307 12.5.3 KAT8/MOF 307 12.5.4 SAS2 and SAS3 308 12.5.5 ESA1 308 12.5.6 Other KATs 308 12.6 KATs in Diseases 309 12.7 KAT Modulators 312 12.7.1 Bisubstrate Inhibitors 313 12.7.2 Natural Products and Synthetic Analogues and Derivatives 315 12.7.3 Synthetic Compounds 321 12.7.4 Compounds Targeting Protein–Protein Interaction Domains 328 12.8 Conclusion 333 References 334 13 Bromodomains: Promising Targets for Drug Discovery 347 Mehrosh Pervaiz, PankajMishra, and Stefan Günther 13.1 Introduction 347 13.2 The Human Bromodomain Family 348 13.2.1 Structural Features of the Human BRD Family 348 13.2.1.1 The Kac Binding Site 348 13.2.1.2 Druggability of the Human BRD Family 350 13.2.2 Functions of Bromodomain-containing Proteins 352 13.3 Bromodomains and Diseases 353 13.3.1 The BET Family 354 13.3.2 Non-BET Proteins 356 13.4 Methods for the Identification of Bromodomain Inhibitors 357 13.4.1 High-throughput Screening (HTS) 357 13.4.2 Fragment-based Lead Discovery 359 13.4.3 Structure-based Drug Design 359 13.4.4 Virtual Screening 362 13.4.4.1 Structure-based Virtual Screening 362 13.4.4.2 Ligand-based Virtual Screening 362 13.4.4.3 Pharmacophore Modeling 363 13.4.4.4 Substructure and Similarity Search 363 13.5 Current Bromodomain Inhibitors 364 13.6 Multi-target Inhibitors 365 13.6.1 Dual Kinase–Bromodomain Inhibitors 365 13.6.2 Dual BET/HDAC Inhibitors 369 13.7 Proteolysis Targeting Chimeras (PROTACs) 369 13.8 Conclusions 371 Acknowledgments 372 References 372 14 Lysine Reader Proteins 383 Johannes Bacher, Dina Robaa, Chiara Luise,Wolfgang Sippl, and Manfred Jung 14.1 Introduction 383 14.2 The Royal Family of Epigenetic Reader Proteins 385 14.2.1 The MBT Domain 385 14.2.2 The PWWP Domain 390 14.2.3 The Tudor Domain 392 14.2.4 The Chromodomain 395 14.3 The PHD Finger Family of Epigenetic Reader Proteins 400 14.4 TheWD40 Repeat Domain Family 402 14.5 Conclusion and Outlook 409 Acknowledgment 409 References 409 15 DNA-modifying Enzymes 421 Martin Roatsch, Dina Robaa,Michael Lübbert,Wolfgang Sippl, and Manfred Jung 15.1 Introduction 421 15.2 DNA Methylation 422 15.3 Further Modifications of Cytosine Bases 424 15.4 DNA Methyltransferases: Substrates and Structural Aspects 426 15.5 Mechanism of Enzymatic DNA Methylation 430 15.6 Physiological Role of DNA Methylation 431 15.7 DNA Methylation in Disease 432 15.8 DNMT Inhibitors 433 15.8.1 Nucleoside-mimicking DNMT Inhibitors 433 15.8.2 Non-nucleosidic DNMT Inhibitors 436 15.9 Therapeutic Applications of DNMT Inhibitors 441 15.10 Conclusion 442 Acknowledgment 443 References 443 16 Parasite Epigenetic Targets 457 Raymond J. Pierce and Jamal Khalife 16.1 Introduction: The Global Problem of Parasitic Diseases and the Need for New Drugs 457 16.2 Parasite Epigenetic Mechanisms 458 16.2.1 DNA Methylation 459 16.2.2 Histone Posttranslational Modifications 460 16.2.3 Histone-modifying Enzymes in Parasites 462 16.2.4 HMEs Validated as Therapeutic Targets 462 16.2.5 Structure-based Approaches for Defining Therapeutic Targets 464 16.3 Development of Epi-drugs for Parasitic Diseases 465 16.3.1 Repurposing of Existing Epi-drugs 466 16.3.2 Candidates from Phenotypic or High-throughput Screens 467 16.3.3 Structure-based Development of Selective Inhibitors 467 16.4 Conclusions 468 Acknowledgments 469 References 469 Index 477

Autorenportrait

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".