Epigenetic Drug Discovery

Cover......Page 1
Title Page......Page 5
Copyright......Page 6
Preface......Page 7
Foreword......Page 9
Contents......Page 11
Part I Introduction – Epigenetics......Page 19
Chapter 1 Epigenetics: Moving Forward......Page 21
1.1 Why This Enormously Increased Interest?......Page 22
1.2 Looking Forward to New Avenues of Epigenetics......Page 23
References......Page 25
Part II General Aspects/Methodologies......Page 29
2.1 Introduction......Page 31
2.2 DNA Methylases: The DNMT3A–DNMT3L–H3 and DNMT1–USP7 Complexes......Page 32
2.3 Histone Arginine Methyltransferases: The PRMT5–MEP50 Complex......Page 34
2.4 Histone Lysine Methyltransferases: The MLL3–RBBP5–ASH2L and the PRC2 Complexes......Page 35
2.5 Histone Lysine Ubiquitinylases: The PRC1 Complex......Page 39
2.6 Histone Lysine Deubiquitinylases: The SAGA Deubiquitination Module......Page 40
2.7 Histone Acetyltransferases: The MSL1 and NUA4 Complexes......Page 42
2.8 Histone Deacetylases: HDAC1–MTA1 and HDAC3–SMRT Complexes and HDAC6......Page 44
2.9 Histone Variants and Histone Chaperones: A Complex and Modular Interplay......Page 46
2.10 ATP‐Dependent Remodelers: CHD1, ISWI, SNF2, and the SNF2‐Nucleosome Complex......Page 49
2.11 Epigenetic Readers: Histone Crotonylation Readers and the 53BP1‐Nucleosome (H2AK15Ub–H4K20me2) Complex......Page 53
2.12 Conclusions......Page 55
References......Page 56
3.1 Introduction......Page 63
3.2.1 Pharmacophore‐based Methods......Page 64
3.2.3 Docking......Page 65
3.2.4 Virtual Screening......Page 66
3.3.1 Zinc‐Dependent HDACs......Page 67
3.3.2 Sirtuins......Page 72
3.4 Histone Methyltransferases......Page 76
3.5 Histone Demethylases......Page 79
3.5.1 LSD1 (KDM1A)......Page 80
3.5.2 Jumonji Histone Demethylases......Page 82
Acknowledgments......Page 84
References......Page 85
4.1 Introduction: Mass Spectrometry Technology Used in Epigenetic Drug Discovery......Page 97
4.1.1 Mass Spectrometry Workflows for the Analysis of Proteins......Page 98
4.1.2 Mass Spectrometry Imaging......Page 101
4.2 Target Identification and Selectivity Profiling: Chemoproteomics......Page 103
4.2.1 Histone Deacetylase and Acetyltransferase Chemoproteomics......Page 105
4.2.3 Demethylase Chemoproteomics......Page 106
4.3.1 Immunoaffinity Purification of Native Protein Complexes......Page 107
4.3.2 Immunoaffinity Purification with Antibodies Against Epitope Tags......Page 108
4.4 Elucidation of a Drug's Mode of Action: Analysis of Histone Posttranslational Modifications by MS‐Based Proteomics......Page 109
4.4.1 Histone Modification MS Workflows......Page 110
4.4.2 Application of Histone MS Workflows to Characterize Epigenetic Drugs......Page 113
4.5.1 Challenges and Trends in MS Analysis of Histone PTMs......Page 115
4.5.3 Mass Spectrometry Imaging of Drug Action......Page 116
References......Page 117
5.1 Introduction......Page 125
5.2.1 Profiling of Substrate Specificities of Histone Code Writers......Page 128
5.2.2 Profiling of Substrate Specificities of Histone Code Erasers......Page 132
5.2.3 Profiling of Binding Specificities of PTM‐specific Antibodies and Histone Code Readers......Page 135
5.2.3.1 Profiling of Specificities of PTM‐specific Antibodies......Page 136
5.2.3.2 Profiling of Binding Specificities of Histone Code Readers......Page 137
5.2.4 Peptide Microarray‐based Identification of Upstream Kinases and Phosphorylation Sites for Epigenetic Targets......Page 139
References......Page 142
6.1 Chemical Probes Are Privileged Reagents for Biological Research......Page 151
6.1.1 Best Practices for the Generation and Selection of Chemical Probes......Page 152
6.1.2 Best Practices for Application of Chemical Probes......Page 154
6.1.3 Cellular Target Engagement......Page 155
6.1.3.2 Affinity Bead‐Based Proteomics......Page 156
6.1.3.4 Bioluminescence Resonance Energy Transfer......Page 157
6.2.1 Histone Acetylation and Bromodomain Chemical Probes......Page 159
6.2.1.1 CBP/p300 Bromodomain Chemical Probes......Page 162
6.3 Summary......Page 165
References......Page 166
Part III Epigenetic Target Classes......Page 171
7.1 Introduction: Histone Deacetylases......Page 173
7.2.1 Types of Inhibitors......Page 176
7.2.2 HDAC Inhibitors in Clinical Use and Development......Page 178
7.3.1 Class I Inhibitors......Page 187
7.3.1.1 HDAC1–3 Inhibitors......Page 188
7.3.1.2 HDAC Inhibitors Targeting HDAC8......Page 191
7.3.2 Class IIa Inhibitors......Page 192
7.3.3 Class IIb......Page 194
7.4 Perspectives......Page 195
References......Page 197
8.2 Biological Functions of Sirtuins in Physiology and Pathology......Page 203
8.3.1.1 Small Molecules......Page 206
8.3.2 SIRT Activators......Page 209
8.4 Summary and Conclusions......Page 210
References......Page 211
9.2 Protein Methylation......Page 219
9.4.1 Inhibitors of H3K9 Methyltransferases......Page 220
9.4.2 Inhibitors of H3K27 Methyltransferases......Page 222
9.4.3 Inhibitors of H3K4 and H3K36 Methyltransferases......Page 224
9.4.4 Inhibitors of H4K20 Methyltransferases......Page 226
9.4.5 Inhibitors of H3K79 Methyltransferases......Page 228
9.5.1 Inhibitors of PRMT1......Page 229
9.5.2 Inhibitors of PRMT3......Page 230
9.5.3 Inhibitors of CARM1......Page 231
9.5.5 Inhibitors of PRMT6......Page 232
References......Page 233
10.1 Introduction......Page 239
10.2 LSDs: Discovery and Mechanistic Features......Page 241
10.3 LSD Substrates......Page 243
10.4 LSD Function and Dysfunction......Page 247
10.5 LSD Inhibitors......Page 250
10.5.1 Irreversible Small Molecule LSD Inhibitors from MAO Inhibitors......Page 251
10.5.2 Reversible Small Molecule LSD Inhibitors......Page 259
10.5.3 Synthetic Macromolecular LSD Inhibitors......Page 266
10.6 Summary......Page 269
References......Page 271
11.1.1 The LSD and JmjC Histone Lysine Demethylases......Page 281
11.1.2 Histone Lysine Methylation and the JmjC‐KDMs......Page 283
11.1.3 The JmjC‐KDMs in Development and Disease......Page 284
11.2 KDM Inhibitor Development Targeting the JmjC Domain......Page 290
11.2.1.2 Bioisosteres of the Conserved 2OG C5‐Carboxylic Acid‐Binding Motif......Page 291
11.2.2 Histone Substrate‐Competitive Inhibitors......Page 293
11.2.3 Allosteric Inhibitors......Page 294
11.2.4.1 KDM4 Subfamily‐Targeted Inhibitors......Page 295
11.2.4.2 KDM4/5 Subfamily‐Targeted Inhibitors......Page 297
11.2.4.3 KDM5 Subfamily‐Targeted Inhibitors......Page 298
11.2.4.4 KDM6 Subfamily‐Targeted Inhibitors......Page 299
11.2.4.6 Generic JmjC‐KDM Inhibitors......Page 300
11.2.5 Selectivity and Potency of JmjC‐KDM Inhibition in Cells......Page 301
11.3.1 Plant Homeodomain Fingers (PHD Fingers)......Page 302
11.4 Conclusions and Future Perspectives......Page 304
References......Page 305
12.1 Introduction......Page 315
12.2 Acetyltransferase Enzymes and Families......Page 316
12.3 The GNAT Superfamily......Page 317
12.3.1 KAT2A/GCN5 and KAT2B/PCAF......Page 319
12.3.2 KAT1/Hat1......Page 321
12.4 KAT3A/CBP and KAT3B/p300 Family......Page 322
12.5.1 KAT5/Tip60......Page 324
12.5.3 KAT8/MOF......Page 325
12.5.6 Other KATs......Page 326
12.6 KATs in Diseases......Page 327
12.7 KAT Modulators......Page 330
12.7.1 Bisubstrate Inhibitors......Page 331
12.7.2 Natural Products and Synthetic Analogues and Derivatives......Page 333
12.7.3 Synthetic Compounds......Page 339
12.7.4 Compounds Targeting Protein–Protein Interaction Domains......Page 346
12.8 Conclusion......Page 351
References......Page 352
13.1 Introduction......Page 365
13.2.1.1 The Kac Binding Site......Page 366
13.2.1.2 Druggability of the Human BRD Family......Page 368
13.2.2 Functions of Bromodomain‐containing Proteins......Page 370
13.3 Bromodomains and Diseases......Page 371
13.3.1 The BET Family......Page 372
13.3.2 Non‐BET Proteins......Page 374
13.4.1 High‐throughput Screening (HTS)......Page 375
13.4.3 Structure‐based Drug Design......Page 377
13.4.4.2 Ligand‐based Virtual Screening......Page 380
13.4.4.4 Substructure and Similarity Search......Page 381
13.5 Current Bromodomain Inhibitors......Page 382
13.6.1 Dual Kinase–Bromodomain Inhibitors......Page 383
13.7 Proteolysis Targeting Chimeras (PROTACs)......Page 387
13.8 Conclusions......Page 389
References......Page 390
14.1 Introduction......Page 401
14.2.1 The MBT Domain......Page 403
14.2.2 The PWWP Domain......Page 408
14.2.3 The Tudor Domain......Page 410
14.2.4 The Chromodomain......Page 413
14.3 The PHD Finger Family of Epigenetic Reader Proteins......Page 418
14.4 The WD40 Repeat Domain Family......Page 420
References......Page 427
15.1 Introduction......Page 439
15.2 DNA Methylation......Page 440
15.3 Further Modifications of Cytosine Bases......Page 442
15.4 DNA Methyltransferases: Substrates and Structural Aspects......Page 444
15.5 Mechanism of Enzymatic DNA Methylation......Page 448
15.6 Physiological Role of DNA Methylation......Page 449
15.7 DNA Methylation in Disease......Page 450
15.8.1 Nucleoside‐mimicking DNMT Inhibitors......Page 451
15.8.2 Non‐nucleosidic DNMT Inhibitors......Page 454
15.9 Therapeutic Applications of DNMT Inhibitors......Page 459
15.10 Conclusion......Page 460
References......Page 461
16.1 Introduction: The Global Problem of Parasitic Diseases and the Need for New Drugs......Page 475
16.2 Parasite Epigenetic Mechanisms......Page 476
16.2.1 DNA Methylation......Page 477
16.2.2 Histone Posttranslational Modifications......Page 478
16.2.4 HMEs Validated as Therapeutic Targets......Page 480
16.2.5 Structure‐based Approaches for Defining Therapeutic Targets......Page 482
16.3 Development of Epi‐drugs for Parasitic Diseases......Page 483
16.3.1 Repurposing of Existing Epi‐drugs......Page 484
16.3.3 Structure‐based Development of Selective Inhibitors......Page 485
16.4 Conclusions......Page 486
References......Page 487
Index......Page 495
EULA......Page 506