Fueled by the expertise of a team of international specialist authors, this first reference on the booming topic covers everything a drug researcher needs to know about targeting epigenetic mechanisms of disease. The first part of the book surveys current methodologies for finding and validating drug candidates that act via epigenetic mechanisms. The second part systematically surveys known and suspected drug targets within the epigenetic machinery, including the discovery and development of vorinostat, the first marketed epigenetic drug.
Wolfgang Sippl is the head of Pharmaceutical and Medicinal Chemistry at the Martin-Luther University of Halle-Wittenberg (Germany). He obtained his Ph.D. in Pharmaceutical Chemistry at University of Dusseldorf and was a post-doctoral fellow at the Universite Louis-Pasteur in Strasbourg (France), where he worked with Camille G. Wermuth. He then took a senior researcher position in Dusseldorf before moving to the University of Halle-Wittenberg as a full professor in 2003. His main interests are focussed on medicinal chemistry, computational chemistry and drug design Manfred Jung is Professor for Pharmaceutical and Medicinal Chemistry at the Albert-Ludwigs University of Freiburg (Germany). He obtained a Ph.D. in Pharmaceutical Chemistry from the University of Marburg, working subsequently as a postdoctoral fellow with T. Durst at the University of Ottawa (Canada). In 1994 he started his own group at the Institute of Pharmaceutical Chemistry at the University of Munster and in 2003 he moved to Freiburg to his current position. His main research focus is the synthesis of enzyme inhibitors and in-vitro assay development in the field of histone modifying enzymes.
PART I: General Aspects and Methodologies NEW FRONTIERS IN EPIGENETIC MODIFICATIONS Introduction DNA Methylation Histone Modifications and the Histone Code Hypothesis Origins of Specificity in Histone Binding Proteins/Modifying Enzymes Histone Modification Cross-Talk Inhibitors of DNMTs and HDACs STRUCTURAL BIOLOGY OF EPIGENETIC TARGETS Introduction Histone Acetyltransferases Histone Deacetylases Sirtuins Histone Methylation Enzymes Histone Demethylases DNA Methyltransferases Concluding Remarks: The Challenge of Structural Studies of Epigenetic Targets COMPUTER- AND STRUCTURE-BASED LEAD IDENTIFICATION FOR EPIGENETIC TARGETS Introduction Computer-Based Methods in Drug Discovery DNA Methyltransferases Histone Deacetylases Histone Acetyltransferases Histone Methyltransferases Histone Demethylases HISTONE MODIFICATION ANALYSIS USING MASS SPECTROMETRY Introduction Histone Molecules Capillary Electrophoresis Reversed Phase Chromatography Mass Spectrometry IN VITRO ASSAYS FOR HISTONE-MODIFYING ENZYMES Introduction Screening Hierarchy General Principles of Screening for Histone-Modifying Enzymes Histone Deacetylases Histone Acetyltransferases Histone Methyltransferases Histone Demethylases EPIGENETIC TARGETS IN DRUG DISCOVERY: CELL-BASED ASSAYS FOR HDAC INHIBITOR HIT VALIDATION Introduction In Vitro Assays for HDAC Inhibitors Cell-Based Assays Biological Function-Based Assays HDAC Isoform Functional Assays Anticancer Activity Perspective CHROMATIN IMMUNOPRECIPITATION CHIP: WET LAB MEETS IN SILICO Background and Overview The Basic Principle of ChIP Different Variations of ChIP Analysis of ChIP Data Data Analysis Examples The Future of ChIP PART II: Epigenetic Target Classes and Inhibitor Development DNA METHYLTRANSFERASE INHIBITORS Introduction DNA Methylation DNA Methyltransferases Biochemical Mechanism of DNA Methylation Physiological Role of DNA Methylation DNA Methylation and Disease DNMT Inhibitors Therapeutic Applications of DNMT Inhibitors HISTONE DEACETYLASE INHIBITORS Introduction Mechanism and X-Ray Crystal Structure Histone Deacetylase Inhibitors NAD-DEPENDENT DEACETYLASES AS THERAPEUTIC TARGETS Historical Perspective and Functions of Sir2 in Yeast Sirtuin Enzymatic Activity and its Modulation by Endogenous Molecules Small Molecule Inhibitors of Sirtuins Small Molecule Activators of Sirtuins SIRT1 as a Therapeutic Target in Metabolic Syndrome and Type 2 Diabetes Neurological Diseases INHIBITORS OF HISTONE ACETYLTRANSFERASES: DISCOVERY AND BIOMEDICAL PERSPECTIVES Introduction HAT Inhibitors HISTONE METHYLTRANSFERASES AS NOVEL DRUG TARGETS Introduction Protein Methylation Histone Demethylation Histone Methyltransferases Histone Methyltransferase Inhibitors HISTONE DEMETHYLASES Introduction Chromatin Histone Methylation and Demethylation Histone Demethylases LSD1/KDM1 JmjC Domain-Containing Demethylases