Medicinal Chemistry Approaches to Personalized Medicine

1. Auflage 2013
ISBN: 978-3-527-33394-3
Verlag: Wiley VCH Verlag GmbH

Buch, Englisch, Band 59, 408 Seiten, Format (B × H): 174 mm x 249 mm, Gewicht: 1000 g

Reihe: Methods and Principles in Medicinal Chemistry

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

Autoren/Hrsg.

Lackey, Karen

Roth, Bruce

Weitere Mitwirkende

Mannhold, Raimund

Kubinyi, Hugo

Folkers, Gerd

Fachgebiete

• Medizin | Veterinärmedizin Medizin | Public Health | Pharmazie | Zahnmedizin Pharmazie
• Technische Wissenschaften Verfahrenstechnik | Chemieingenieurwesen | Biotechnologie Pharmazeutische Technologie
• Naturwissenschaften Chemie Chemie Allgemein Pharmazeutische Chemie, Medizinische Chemie

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

Über Autor(innen)

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.