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Medicinal Chemistry Approaches to Personalized Medicine

Methods & Principles in Medicinal Chemistry, Band 59 1. Aufl.

von: Karen Lackey, Bruce Roth, Raimund Mannhold, Hugo Kubinyi, Gerd Folkers
144,99 €
Verlag:	Wiley-VCH
Format:	EPUB
Veröffentl.:	22.11.2013
ISBN/EAN:	9783527677276
Sprache:	englisch
Anzahl Seiten:	408

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Titelbeschreibung

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

Inhaltsverzeichnis

Foreword Preface A Personal Foreword Acronyms MEDICINAL CHEMISTRY APPROACHES TO CREATING TARGETED MEDICINES Introduction Role of Medicinal Chemistry in Drug Discovery Evolution of Molecular Design for Subsets of Patiens Combinations for Effective Therapies Biomarkers in Targeting Patiens Emerging Field of Epigenetics Systems Chemical Biology Theranostics and Designing Drug Delivery Systems Rapid Progress in Further Personalizing Medicine Expected DISCOVERY OF PREDICTIVE BIOMARKERS FOR ANTICANCER DRUGS Introduction "Oncogene Addiction" as a Paradigm for Clinical Implementation of Predictive Biomarkers Cancer Cell Lines as a Model System for Discovery of Predictive Biomarkers Modeling Drug Resistance to Discover Predictive Biomarkers Discovery of Predictive Biomarkers in the Context of Treatment Combinations Discovery of Predictive Biomarkers for Antiangiogenic Agents Gene Expression Signatures as Predictive Biomarkers Current Challenges in Discovering Predictive Biomarkers Future Perspective CRIZOTINIB Introduction Discovery of Crizotinib (PF-02341066) Kinase Selectivity of Crizotinib Pharmacology of Crizotinib Human Clinical Efficacies of Crizotinib Summary DISCOVERY AND DEVELOPMENT OF VEMURAFENIB: FIRST-IN-CLASS INHIBITOR OF MUTANT BRAF FOR THE TREATMENT OF CANCER Background Discovery and Development of Vemurafenib (PLX4032) Pharmacology Clinical Efficacy and Safety Companion Diagnostic (cobas 4800) Development Synthesis Summary TARGETING BASAL-CELL CARCINOMA: DISCOVERY AND DEVELOPMENT OF VISMODEGIB (GDC-0449), A FIRST-IN-CLASS INHIBITOR OF THE HEDGEHOG PATHWAY Introduction Hedgehog and Basal-Cell Carcinoma Cyclopamine as an SMO Antagonist Small-Molecule Inhibitors of SMO Preclinical Characterization of Vismodegib Vismodegib Clinical Experience in Phase 1 G-QUADRUPLEXES AS THERAPEUTIC TARGETS IN CANCER Introduction Quadruplex Fundamentals Genomic Quadruplexes Quadruplexes in Human Telomeres Quadruplexes as Anticancer Targets - Evidence from In Vivo Studies Native Quadruplex Structures Quadruplex-Small-Molecule Structures Developing Superior Quadruplex-Binding Ligands Conclusions IDENTIFYING ACTIONABLE TARGETS IN CANCER PATIENS Introduction and Background Overview of Genomic Sequencing and Its Impact on the Identification of Actionable Mutations Actionable Targets by Clinical Molecular Profiling: The OICR/PMH Experience Some Exeriences of Other Clinical Oncology Molecular Profiling Studies Identifying Secondary and Novel Mutations through Molecular Profiling Understanding and Targeting Resistance Mutations: A Challenge and an Opportunity for NGS Concluding Remarks and Future Perspectives DNA DAMAGE REPAIR PATHWAYS AND SYNTHETIC LETHALITY Introduction DNA Damage Response Synthetic Lethality Lead Case Study: PARP Inhibitors Additional Case Studies Screening for Synthetic Lethality Contextual Synthetic Lethality Screening Cancer Stem Cells Conclusions and Future Directions AMYLOID CHEMICAL PROBES AND THERANOSTICS: STEPS TOWARD PERSONALIZED MEDICINE IN NEURODEGENERATIVE DISEASES Introduction Amyloid Plaques as the Biomarker in AD Detecting Amyloid Plaques in Patiens: From Alois Alzheimer to Amyvid and Beyond Same Causes, Same Imaging Agents? Theranosticcs in AD Conclusions and Perspectives FROM HUMAN GENETICS TO DRUG CANDIDATES: AN INDUSTRIAL PERSPECTIVE ON LRRK2 INHIBITION AS A TREATMENT FOR PARKINSON'S DISEASE Introduction Biochemical Studies of LRRK2 Function Cellular Studies in LRRK2 Function Animal Models of LRRK2 Function Clinical Studies of LRRK2-Associated PD and Future Prospects Small-Molecule Inhibitors of LRRK2 Structural Models of the LRRK2 Kinase Domain Strategies Used to Identify LRRK2 Kinase Inhibitors (Overview) Conclusions THERAPEUTIC POTENTIAL OF KINASES IN ASTHMA Introduction Mitogen-Activated Protein Kinases Nonreceptor Protein Tyrosine Kinases Receptor Tyrosine Kinases Phosphatidylinositol-3 Kinases AGC Kinases IkB Kinase Other Kinases Conclusions: Future Directions DEVELOPING TARGETED PET TRACERS IN THE ERA OF PERSONALIZED MEDICINE Imaging and Pharmacodynamics Biomarkers in Drug Development General Considerations for Development of 11C- and 18F-labeled PET Tracers Radiolabeling Compounds with 11C Radiolabeling Compounds wiht 18F PET Imaging in the Clinic, Research, and Drug Development PET Tracer Kinetic Modeling for Quantification of Tracer Uptake Concluding Remarks MEDICINAL CHEMISTRY IN THE CONTEXT OF THE HUMAN GENOME Introduction Drugs Targeting Kinases Drugs Targeting Phosphatases In silico-Based Lead Discovery in the GPCR Family Targeting Epigenetic Regulation: Histone Demethylases Targeting Epigenetic Regulation: Histone Deacetylases A Family-Wide Approach to Poly(ADP-Ribose) Polymerases Future Drug Target Superfamilies: Ubiquitination and Deubiquitination Summary and Outlook Index

Autorenportrait

Karen Lackey is currently the founder and Chief Scientific Officer of JanAush, a drug discovery company focused on creating life-saving medicines in inflammation, oncology, and kinase and signal inhibition. She joined Hoffmann-La Roche in 2010 as Vice President and Head of Medicinal Chemistry at the Nutley, NJ (USA) site, where she was responsible for oncology, inflammation, virology and new technologies until the site closure in 2013. In her previous role, she was the Vice President of Chemistry, Molecular Discovery Research for GlaxoSmithKline. Most importantly, she played an active role in the discovery of the dual erbB2/EGFR tyrosine kinase inhibitor, lapatinib, currently marketed as Tykerb. Karen has over 85 publications and patents, principally covering oncology, inflammation, kinase inhibition, gene family molecular design and cellular signaling. Bruce Roth is currently Vice President of Discovery Chemistry in Genentech Research and Early Development at South San Francisco (USA). Prior to joining Genentech in 2007, he was Vice President of Discovery Chemistry at the Pfizer Global Research and Development Ann Arbor site. Bruce began his career as a medicinal chemist at Warner-Lambert, Parke-Davis in 1982 and is best known as the inventor of Lipitor (atorvastatin calcium), for which he has received numerous awards, including the 2003 American Chemical Society Award for Creative Invention, the 2003 Gustavus J. Esselen Award and the 2013 Perkin Medal. In 2008 he was named one of the American Chemical Society's Heroes in Chemistry.