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Medicinal Chemistry Approaches to Personalized Medicine

Medicinal Chemistry Approaches to Personalized Medicine

Karen Lackey (Editor), Bruce Roth (Editor), Raimund Mannhold (Series Editor), Hugo Kubinyi (Series Editor), Gerd Folkers (Series Editor)

ISBN: 978-3-527-67727-6

Nov 2013

408 pages

$156.99

Description

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
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