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Edited by two renowned medicinal chemists who have pioneered the development of personalized therapies in their respective fields, this authoritative analysis of what is already possible is the first of its kind, and the only one to focus on drug development issues.Numerous case studies from the first generation of "personalized drugs" are presented, highlighting the challenges and opportunities for pharmaceutical development. While the majority of these examples are taken from the field of cancer treatment, other key emerging areas, such as neurosciences and inflammation, are also covered.With its careful balance of current and future approaches, this handbook is a prime knowledge source for every drug developer, and one that will remain up to date for some time to come.From the content:* Discovery of Predictive Biomarkers for Anticancer Drugs* Discovery and Development of Vemurafenib* Targeting Basal-Cell Carcinoma* G-Quadruplexes as Therapeutic Targets in Cancer* From Human Genetics to Drug Candidates: An Industrial Perspective on LRRK2 Inhibition as a Treatment for Parkinson's Disease* Therapeutic Potential of Kinases in Asthma* DNA Damage Repair Pathways and Synthetic Lethality* Medicinal Chemistry in the Context of the Human Genomeand many more
Sommario
ForewordPrefaceA Personal ForewordAcronymsMEDICINAL CHEMISTRY APPROACHES TO CREATING TARGETED MEDICINESIntroductionRole of Medicinal Chemistry in Drug DiscoveryEvolution of Molecular Design for Subsets of PatiensCombinations for Effective TherapiesBiomarkers in Targeting PatiensEmerging Field of EpigeneticsSystems Chemical BiologyTheranostics and Designing Drug Delivery SystemsRapid Progress in Further Personalizing Medicine ExpectedDISCOVERY OF PREDICTIVE BIOMARKERS FOR ANTICANCER DRUGSIntroduction"Oncogene Addiction" as a Paradigm for Clinical Implementation of Predictive BiomarkersCancer Cell Lines as a Model System for Discovery of Predictive BiomarkersModeling Drug Resistance to Discover Predictive BiomarkersDiscovery of Predictive Biomarkers in the Context of Treatment CombinationsDiscovery of Predictive Biomarkers for Antiangiogenic AgentsGene Expression Signatures as Predictive BiomarkersCurrent Challenges in Discovering Predictive BiomarkersFuture PerspectiveCRIZOTINIBIntroductionDiscovery of Crizotinib (PF-02341066)Kinase Selectivity of CrizotinibPharmacology of CrizotinibHuman Clinical Efficacies of CrizotinibSummaryDISCOVERY AND DEVELOPMENT OF VEMURAFENIB: FIRST-IN-CLASS INHIBITOR OF MUTANT BRAF FOR THE TREATMENT OF CANCERBackgroundDiscovery and Development of Vemurafenib (PLX4032)PharmacologyClinical Efficacy and SafetyCompanion Diagnostic (cobas 4800) DevelopmentSynthesisSummaryTARGETING BASAL-CELL CARCINOMA: DISCOVERY AND DEVELOPMENT OF VISMODEGIB (GDC-0449), A FIRST-IN-CLASS INHIBITOR OF THE HEDGEHOG PATHWAYIntroductionHedgehog and Basal-Cell CarcinomaCyclopamine as an SMO AntagonistSmall-Molecule Inhibitors of SMOPreclinical Characterization of VismodegibVismodegib Clinical Experience in Phase 1G-QUADRUPLEXES AS THERAPEUTIC TARGETS IN CANCERIntroductionQuadruplex FundamentalsGenomic QuadruplexesQuadruplexes in Human TelomeresQuadruplexes as Anticancer Targets - Evidence from In Vivo StudiesNative Quadruplex StructuresQuadruplex-Small-Molecule StructuresDeveloping Superior Quadruplex-Binding LigandsConclusionsIDENTIFYING ACTIONABLE TARGETS IN CANCER PATIENSIntroduction and BackgroundOverview of Genomic Sequencing and Its Impact on the Identification of Actionable MutationsActionable Targets by Clinical Molecular Profiling: The OICR/PMH ExperienceSome Exeriences of Other Clinical Oncology Molecular Profiling StudiesIdentifying Secondary and Novel Mutations through Molecular ProfilingUnderstanding and Targeting Resistance Mutations: A Challenge and an Opportunity for NGSConcluding Remarks and Future PerspectivesDNA DAMAGE REPAIR PATHWAYS AND SYNTHETIC LETHALITYIntroductionDNA Damage ResponseSynthetic LethalityLead Case Study: PARP InhibitorsAdditional Case StudiesScreening for Synthetic LethalityContextual Synthetic Lethality ScreeningCancer Stem CellsConclusions and Future DirectionsAMYLOID CHEMICAL PROBES AND THERANOSTICS: STEPS TOWARD PERSONALIZED MEDICINE IN NEURODEGENERATIVE DISEASESIntroductionAmyloid Plaques as the Biomarker in ADDetecting Amyloid Plaques in Patiens: From Alois Alzheimer to Amyvid and BeyondSame Causes, Same Imaging Agents?Theranosticcs in ADConclusions and PerspectivesFROM HUMAN GENETICS TO DRUG CANDIDATES: AN INDUSTRIAL PERSPECTIVE ON LRRK2 INHIBITION AS A TREATMENT FOR PARKINSON'S DISEASEIntroductionBiochemical Studies of LRRK2 FunctionCellular Studies in LRRK2 FunctionAnimal Models of LRRK2 FunctionClinical Studies of LRRK2-Associated PD and Future ProspectsSmall-Molecule Inhibitors of LRRK2Structural Models of the LRRK2 Kinase DomainStrategies Used to Identify LRRK2 Kinase Inhibitors (Overview)ConclusionsTHERAPEUTIC POTENTIAL OF KINASES IN ASTHMAIntroductionMitogen-Activated Protein KinasesNonreceptor Protein Tyrosine KinasesReceptor Tyrosine KinasesPhosphatidylinositol-3 KinasesAGC KinasesIkB KinaseOther KinasesConclusions: Future DirectionsDEVELOPING TARGETED PET TRACERS IN THE ERA OF PERSONALIZED MEDICINEImaging and Pharmacodynamics Biomarkers in Drug DevelopmentGeneral Considerations for Development of 11C- and 18F-labeled PET TracersRadiolabeling Compounds with 11CRadiolabeling Compounds wiht 18FPET Imaging in the Clinic, Research, and Drug DevelopmentPET Tracer Kinetic Modeling for Quantification of Tracer UptakeConcluding RemarksMEDICINAL CHEMISTRY IN THE CONTEXT OF THE HUMAN GENOMEIntroductionDrugs Targeting KinasesDrugs Targeting PhosphatasesIn silico-Based Lead Discovery in the GPCR FamilyTargeting Epigenetic Regulation: Histone DemethylasesTargeting Epigenetic Regulation: Histone DeacetylasesA Family-Wide Approach to Poly(ADP-Ribose) PolymerasesFuture Drug Target Superfamilies: Ubiquitination and DeubiquitinationSummary and OutlookIndex
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Hugo Kubinyi gehört seit 1985 der BASF AG an, wo Kombinatorische Chemie, Molecular Modelling und Wirkstoffdesign zu seinen Tätigkeitsfeldern zählten. Sein Spezialgebiet sind Struktur-Wirkungs-Beziehungen und QSAR-Methoden.
Gerd Folkers is professor of pharmaceutical chemistry at the ETH Zürich since 1991. He studied pharmacy at the University of Bonn and earned his Ph.D. on structure-activity relationships of desapurines. He then moved to the University of Tübingen, where he completed his habilitation in pharmaceutical chemistry. During a stay with H.-D. Hoeltje in Bern, he studied new research methods in computer-aided molecular design and expanded this knowledge during other stays with T. Blundell at the Birkbeck College and E. Meyer at Texas A&M University.The focus of his research is the molecular interaction between drugs and their binding sites. Besides his work on the molecular mechanism of "conventional" nucleoside therapeutics against virus infections and cancer, his special interest has shifted to immuno-therapeutics.
Riassunto
Edited by two renowned medicinal chemists who have pioneered the development of personalized therapies in their respective fields, this authoritative analysis of what is already possible is the first of its kind, and the only one to focus on drug development issues.
Numerous case studies from the first generation of "personalized drugs" are presented, highlighting the challenges and opportunities for pharmaceutical development. While the majority of these examples are taken from the field of cancer treatment, other key emerging areas, such as neurosciences and inflammation, are also covered.
With its careful balance of current and future approaches, this handbook is a prime knowledge source for every drug developer, and one that will remain up to date for some time to come.
From the content:
* Discovery of Predictive Biomarkers for Anticancer Drugs
* Discovery and Development of Vemurafenib
* Targeting Basal-Cell Carcinoma
* G-Quadruplexes as Therapeutic Targets in Cancer
* From Human Genetics to Drug Candidates: An Industrial Perspective on LRRK2 Inhibition as a Treatment for Parkinson's Disease
* Therapeutic Potential of Kinases in Asthma
* DNA Damage Repair Pathways and Synthetic Lethality
* Medicinal Chemistry in the Context of the Human Genome
and many more
