Epigenetic Targets In Drug Discovery

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 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.

"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)

List of Contributors.
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.