Epigenetic Targets in Drug Discovery

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 designManfred 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.

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.

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.
After a general introduction, the second part of the book surveys current methodologies for finding and validating drug candidates that act via epigenetic mechanisms. The third and final 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.

PART I: General Aspects and MethodologiesNEW FRONTIERS IN EPIGENETIC MODIFICATIONSIntroductionDNA MethylationHistone Modifications and the Histone Code HypothesisOrigins of Specificity in Histone Binding Proteins/Modifying EnzymesHistone Modification Cross-TalkInhibitors of DNMTs and HDACsSTRUCTURAL BIOLOGY OF EPIGENETIC TARGETSIntroductionHistone AcetyltransferasesHistone DeacetylasesSirtuinsHistone Methylation EnzymesHistone DemethylasesDNA MethyltransferasesConcluding Remarks: The Challenge of Structural Studies of Epigenetic TargetsCOMPUTER- AND STRUCTURE-BASED LEAD IDENTIFICATION FOR EPIGENETIC TARGETSIntroductionComputer-Based Methods in Drug DiscoveryDNA MethyltransferasesHistone DeacetylasesHistone AcetyltransferasesHistone MethyltransferasesHistone DemethylasesHISTONE MODIFICATION ANALYSIS USING MASS SPECTROMETRYIntroductionHistone MoleculesCapillary ElectrophoresisReversed Phase ChromatographyMass SpectrometryIN VITRO ASSAYS FOR HISTONE-MODIFYING ENZYMESIntroductionScreening HierarchyGeneral Principles of Screening for Histone-Modifying EnzymesHistone DeacetylasesHistone AcetyltransferasesHistone MethyltransferasesHistone DemethylasesEPIGENETIC TARGETS IN DRUG DISCOVERY: CELL-BASED ASSAYS FOR HDAC INHIBITOR HIT VALIDATIONIntroductionIn Vitro Assays for HDAC InhibitorsCell-Based AssaysBiological Function-Based AssaysHDAC Isoform Functional AssaysAnticancer ActivityPerspectiveCHROMATIN IMMUNOPRECIPITATION CHIP: WET LAB MEETS IN SILICOBackground and OverviewThe Basic Principle of ChIPDifferent Variations of ChIPAnalysis of ChIP DataData Analysis ExamplesThe Future of ChIPPART II: Epigenetic Target Classes and Inhibitor DevelopmentDNA METHYLTRANSFERASE INHIBITORSIntroductionDNA MethylationDNA MethyltransferasesBiochemical Mechanism of DNA MethylationPhysiological Role of DNA MethylationDNA Methylation and DiseaseDNMT InhibitorsTherapeutic Applications of DNMT InhibitorsHISTONE DEACETYLASE INHIBITORSIntroductionMechanism and X-Ray Crystal StructureHistone Deacetylase InhibitorsNAD-DEPENDENT DEACETYLASES AS THERAPEUTIC TARGETSHistorical Perspective and Functions of Sir2 in YeastSirtuin Enzymatic Activity and its Modulation by Endogenous MoleculesSmall Molecule Inhibitors of SirtuinsSmall Molecule Activators of SirtuinsSIRT1 as a Therapeutic Target in Metabolic Syndrome and Type 2 DiabetesNeurological DiseasesINHIBITORS OF HISTONE ACETYLTRANSFERASES: DISCOVERY AND BIOMEDICAL PERSPECTIVESIntroductionHAT InhibitorsHISTONE METHYLTRANSFERASES AS NOVEL DRUG TARGETSIntroductionProtein MethylationHistone DemethylationHistone MethyltransferasesHistone Methyltransferase InhibitorsHISTONE DEMETHYLASESIntroductionChromatinHistone Methylation and DemethylationHistone DemethylasesLSD1/KDM1JmjC Domain-Containing Demethylases