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《Epigenetic Targets in Drug Discovery》
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Preface. A Personal Foreword. Part One General Aspects and Methodologies. 1 New Frontiers in Epigenetic Modifications (Adam L. Garske and John M. Denu). 1.1 Introduction. 1.2 DNA Methylation. 1.3 Histone Modifications and the Histone Code Hypothesis. 1.4 Origins of Specificity in Histone Binding Proteins/Modifying Enzymes. 1.5 Histone Modification Cross-talk. 1.6 Inhibitors of DNMTs and HDACs. 1.7 Conclusions. References. 2 Structural Biology of Epigenetic Targets (Christophe Romier, Jean-Marie Wurtz, Jean-Paul Renaud, and Jean Cavarelli). 2.1 Introduction. 2.2 Histone Acetyltransferases. 2.3 Histone Deacetylases. 2.4 Sirtuins. 2.5 Histone Methylation Enzymes. 2.6 Histone Demethylases. 2.7 DNA Methyltransferases. 2.8 Concluding Remarks: the Challenge of Structural Studies of Epigenetic Targets. References. 3 Computer- and Structure-Based Lead Identification for Epigenetic Targets (Ralf Heinke, Urszula Uciechowska, and Wolfgang Sippl). 3.1 Introduction. 3.2 Computer-Based Methods in Drug Discovery. 3.3 DNA Methyltransferases. 3.4 Histone Deacetylases. 3.5 Histone Acetyltransferases. 3.6 Histone Methyltransferases. 3.7 Histone Demethylases. 3.8 Summary. References. 4 Histone Modification Analysis Using Mass Spectrometry (Ana Villar-Garea and Axel Imhof). 4.1 Introduction. 4.2 Histone Molecules. 4.3 Capillary Electrophoresis. 4.4 Reversed Phase Chromatography. 4.5 Mass Spectrometry. References. 5 In Vitro Assays for Histone-Modifying Enzymes (Alexander-Thomas Hauser and Manfred Jung). 5.1 Introduction. 5.2 Screening Hierarchy. 5.3 General Principles of Screening for Histone-Modifying Enzymes. 5.4 Histone Deacetylases. 5.5 Histone Acetyltransferases. 5.6 Histone Methyltransferases. 5.7 Histone Demethylases. 5.8 Conclusion. References. 6 Epigenetic Targets in Drug Discovery: Cell-Based Assays for HDAC Inhibitor Hit Validation (Mira Jung, Kwon-Jeong Yong, Alfredo Velena, and Sung Lee). 6.1 Introduction. 6.2 In Vitro Assays for HDAC Inhibitors. 6.3 Cell-Based Assays. 6.4 Biological Function-Based Assays. 6.5 HDAC Isoform Functional Assays. 6.6 Anticancer Activity. 6.7 Perspective. References. 7 Chromatin Immunoprecipitation ChIP: Wet Lab Meets In Silico (Martin Seifert and Robert Schneider). 7.1 Background and Overview. 7.1.1 Chromatin and DNA Organization. 7.1.2 Chromatin Immunoprecipitation as a Powerful Method to Study Chromatin. 7.2 The Basic Principle of ChIP. 7.3 Different Variations of ChIP. 7.4 Analysis of ChIP Data. 7.5 Data Analysis Examples. 7.6 The Future of ChIP. References. Part Two Epigenetic Target Classes and Inhibitor Development. 8 DNA Methyltransferase Inhibitors (Wolfgang Sippl and Manfred Jung). 8.1 Introduction. 8.2 DNA Methylation. 8.3 DNA Methyltransferases. 8.4 Biochemical Mechanism of DNA Methylation. 8.5 Physiological Role of DNA Methylation. 8.6 DNA Methylation and Disease. 8.7 DNMT Inhibitors. 8.8 Therapeutic Applications of DNMT Inhibitors. 8.9 Conclusion. References. 9 Histone Deacetylase Inhibitors (Philip Jones). 9.1 Introduction. 9.2 Mechanism and X-Ray Crystal Structure. 9.3 Histone Deacetylase Inhibitors. 9.4 Conclusions. References. 10 NAD-Dependent Deacetylases as Therapeutic Targets (Hongzhe Li, Julian Simon, and Antonio Bedalov). 10.1 Historical Perspective and Functions of Sir2 in Yeast. 10.2 Sirtuin Enzymatic Activity and its Modulation by Endogenous Molecules. 10.3 Small Molecule Inhibitors of Sirtuins. 10.4 Small Molecule Activators of Sirtuins. 10.5 SIRT1 as a Therapeutic Target in Metabolic Syndrome and Type 2 Diabetes. 10.6 Neurological Diseases. 10.7 Conclusion. References. 11 Inhibitors of Histone Acetyltransferases: Discovery and Biomedical Perspectives (Margarete von Wantoch Rekowski and Athanassios Giannis). 11.1 Introduction. 11.2 HAT Inhibitors. 11.3 Summary. References. 12 Histone Methyltransferases as Novel Drug Targets (Manfred Jung). 12.1 Introduction. 12.2 Protein Methylation. 12.3 Histone Demethylation. 12.4 Histone Methyltransferases. 12.5 Histone Methyltransferase Inhibitors. 12.6 Concluding Remarks. References. 13 Histone Demethylases (Rasmus P. Clausen, Marianne T. Pedersen, and Kristian Helin). 13.1 Introduction. 13.2 Chromatin. 13.3 Histone Methylation and Demethylation. 13.4 Histone Demethylases. 13.5 LSD1/KDM1. 13.5.1 Inhibitors of LSD1. 13.6 JmjC Domain-Containing Demethylases. 13.7 Summary. References. Index. |
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