Epigenetic Drug Discovery

Presents new targets and strategies for one of the most exciting frontiers in pharmaceutical research Epigenetic Drug Discovery provides a broad overview of epigenetic approaches in drug research, combining methods and strategies with individual targets. 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. The second part of Epigenetic Drug Discovery discusses recently developed methods for examining epigenetic targets, as well as new structural biology and computational approaches. Topics include the structural biology of epigenetic targets, computer-based approaches, mass spectrometry approaches, peptide microarrays for epigenetic targets, and chemical probe development. The third part revisits some of the early epigenetic targets and adds a number of new and still largely unexplored targets, such as sirtuins, methyl-lysine reader proteins, and parasitic targets. It also covers HDAC inhibitors, methyltransferases, demethylases LSD1 and JMJD, histone acetyltransferases, BRD bromodomains, and DNA modifying enzymes. -The latest strategies and targets for epigenetic drug discovery -Tailored to the needs of drug developers working in small and large pharmaceutical companies -Offers comprehensive coverage of the subject and all the techniques and applications within the field Epigenetic Drug Discovery is an important resource for medicinal chemists, pharmaceutical researchers, biochemists, molecular biologists, and molecular geneticists.

Auteur
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".

Résumé
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.

Contenu

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 DNMT3ADNMT3LH3 and DNMT1USP7 Complexes 14

2.3 Histone Arginine Methyltransferases:The PRMT5MEP50 Complex 16

2.4 Histone Lysine Methyltransferases:The MLL3RBBP5ASH2L 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: HDAC1MTA1 and HDAC3SMRT 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 (H2AK15UbH4K20me2) 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 <p&g...