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Epigenetic Targets in Drug Discovery, Volume 42

Wolfgang Sippl (Editor), Manfred Jung (Editor), Raimund Mannhold (Series Editor), Hugo Kubinyi (Series Editor), Gerd Folkers (Series Editor)
ISBN: 978-3-527-32355-5
314 pages
August 2009
Epigenetic Targets in Drug Discovery, Volume 42 (3527323554) cover image
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.
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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


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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 Düsseldorf and was a post-doctoral fellow at the Université Louis-Pasteur in Strasbourg (France), where he worked with Camille G. Wermuth. He then took a senior researcher position in Düsseldorf 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 Münster 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.
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"The book provides an overview about the ‘current methodologies for finding and validating drug candidates acting on epigenetic mechanisms.'" (RoSearch, December 2010)

"Provides a fresh overview within the epigenetic area. ... Effective in combining basic knowledge, methodologies, and drug discoveries in a field that is expanding daily. To the best of my knowledge, this is the first compendium that has these characteristics." (ChemMedChem, 2010)

"Authoritative and comprehensive." (ChemBioChem, October 2009)

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