Epigenetic Targets in Drug Discovery / Edition 1

Epigenetic Targets in Drug Discovery / Edition 1

by Wolfgang Sippl
     
 

The genes that make up our genome are not static entities but undergo a complex modification process that results in certain genes being switched on or off, depending on the state of the cell. This so-called epigenetic regulation is now known in enough detail to allow its specific interference via targeted drugs, strengthening the fight against such human diseases

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Overview

The genes that make up our genome are not static entities but undergo a complex modification process that results in certain genes being switched on or off, depending on the state of the cell. This so-called epigenetic regulation is now known in enough detail to allow its specific interference via targeted drugs, strengthening the fight against such human diseases as cancer and neurodegeneration with an epigenetic component.
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 coverage of the first successful drug candidates available for these novel targets.

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Product Details

ISBN-13:
9783527323555
Publisher:
Wiley
Publication date:
08/11/2009
Series:
Methods and Principles in Medicinal Chemistry Series, #42
Pages:
314
Product dimensions:
6.90(w) x 9.60(h) x 0.80(d)

Table of Contents

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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