Overview

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 ...
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Medicinal Chemistry Approaches to Personalized Medicine, Volume 59

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Overview

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
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Product Details

Meet the Author

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.
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Table of Contents

List of Contributors XI

Foreword XV

Preface XIX

A Personal Foreword XXI

Acronyms XXIII

1 Medicinal Chemistry Approaches to Creating Targeted Medicines 1
Bruce D. Roth and Karen Lackey

1.1 Introduction 1

1.2 Role of Medicinal Chemistry in Drug Discovery 2

1.3 Evolution of Molecular Design for Subsets of Patients 4

1.4 Combinations for Effective Therapies 6

1.5 Biomarkers in Targeting Patients 9

1.6 Emerging Field of Epigenetics 9

1.7 Systems Chemical Biology 10

1.8 Theranostics and Designing Drug Delivery Systems 12

1.9 Rapid Progress in Further Personalizing Medicine Expected 15

References 18

2 Discovery of Predictive Biomarkers for Anticancer Drugs 21
Richard M. Neve, Lisa D. Belmont, Richard Bourgon, Marie Evangelista, Xiaodong Huang, Maike Schmidt, Robert L. Yauch, and Jeffrey Settleman

2.1 Introduction 21

2.2 “Oncogene Addiction” as a Paradigm for Clinical Implementation of Predictive Biomarkers 24

2.3 Cancer Cell Lines as a Model System for Discovery of Predictive Biomarkers 28

2.3.1 Historical Application of Cell Lines in Cancer Research 28

2.3.2 Biomarker Discovery Using Cell Line Models 29

2.3.3 Cell Lines as Models of Human Cancer 31

2.3.4 Challenges and Limitations of Cell Line Models 32

2.4 Modeling Drug Resistance to Discover Predictive Biomarkers 33

2.5 Discovery of Predictive Biomarkers in the Context of Treatment Combinations 38

2.6 Discovery of Predictive Biomarkers for Antiangiogenic Agents 42

2.6.1 Challenges 43

2.6.2 Pathway Activity as a Predictor of Drug Efficacy 44

2.6.3 Predicting Inherent Resistance 45

2.6.4 On-Treatment Effects as a Surrogate of Drug Efficacy 45

2.6.5 Summary 46

2.7 Gene Expression Signatures as Predictive Biomarkers 47

2.7.1 Signature Discovery: Unsupervised Clustering 47

2.7.2 Diagnostic Development: Supervised Classification 48

2.7.3 Summary 50

2.8 Current Challenges in Discovering Predictive Biomarkers 51

2.8.1 Access to Tumor Cells Is Limited during Treatment 51

2.8.2 Drivers and Passengers 53

2.8.3 Epigenetic Regulation Adds Another Layer of Complexity 54

2.8.4 Many Oncoproteins and Tumor Suppressors Undergo Regulatory Posttranslational Modifications 55

2.9 Future Perspective 56

References 57

3 Crizotinib 71
Jean Cui, Robert S. Kania, and Martin P. Edwards

3.1 Introduction 71

3.2 Discovery of Crizotinib (PF-02341066) [40] 74

3.3 Kinase Selectivity of Crizotinib 77

3.4 Pharmacology of Crizotinib [45,46] 78

3.5 Human Clinical Efficacies of Crizotinib 80

3.6 Summary 83

References 85

4 Discovery and Development of Vemurafenib: First-in-Class Inhibitor of Mutant BRAF for the Treatment of Cancer 91
Prabha Ibrahim, Jiazhong Zhang, Chao Zhang, James Tsai, Gaston Habets, and Gideon Bollag

4.1 Background 91

4.2 Discovery and Development of Vemurafenib (PLX4032) 92

4.3 Pharmacology 95

4.4 Clinical Efficacy and Safety 96

4.5 Companion Diagnostic (cobas 4800) Development 96

4.6 Synthesis 96

4.6.1 Discovery Route(s) 96

4.6.2 Process Route 97

4.7 Summary 98

References 98

5 Targeting Basal-Cell Carcinoma: Discovery and Development of Vismodegib (GDC-0449), a First-in-Class Inhibitor of the Hedgehog Pathway 101
James C. Marsters Jr. and Harvey Wong

5.1 Introduction 101

5.2 Hedgehog and Basal-Cell Carcinoma 102

5.3 Cyclopamine as an SMO Antagonist 102

5.4 Small-Molecule Inhibitors of SMO 103

5.5 Preclinical Characterization of Vismodegib 107

5.5.1 Plasma Protein Binding and Blood Plasma Partitioning 107

5.5.2 In Vitro and Exploratory In Vivo Metabolism of Vismodegib 108

5.5.3 Drug–Drug Interaction Potential 109

5.5.4 Preclinical Pharmacokinetics 109

5.5.5 Predicted Human Pharmacokinetics 110

5.5.6 Summary 112

5.6 Vismodegib Clinical Experience in Phase I 112

References 114

6 G-Quadruplexes as Therapeutic Targets in Cancer 117
Stephen Neidle

6.1 Introduction 117

6.2 Quadruplex Fundamentals 117

6.3 Genomic Quadruplexes 119

6.4 Quadruplexes in Human Telomeres 120

6.5 Quadruplexes as Anticancer Targets – Evidence fromIn Vivo Studies 123

6.6 Native Quadruplex Structures 125

6.7 Quadruplex–Small-Molecule Structures 130

6.8 Developing Superior Quadruplex-Binding Ligands 130

6.9 Conclusions 134

References 136

7 Identifying Actionable Targets in Cancer Patients 147
David Uehling, Janet Dancey, Andrew M.K. Brown, John McPherson, and Rima Al-awar

7.1 Introduction and Background 147

7.2 Overview of Genomic Sequencing and Its Impact on the Identification of Actionable Mutations 149

7.3 Actionable Targets by Clinical Molecular Profiling: the OICR/PMH Experience 157

7.4 Some Experiences of Other Clinical Oncology Molecular Profiling Studies 163

7.5 Identifying Secondary and Novel Mutations through Molecular Profiling 165

7.6 Understanding and Targeting Resistance Mutations: a Challenge and an Opportunity for NGS 166

7.6.1 Identification and Treatment Strategies for Actionable Secondary Resistance Mutations 169

7.6.2 Toward the Identification of Actionable Primary Resistance Mutations 173

7.7 Concluding Remarks and Future Perspectives 175

References 178

8 DNA Damage Repair Pathways and Synthetic Lethality 183
Simon Ward

8.1 Introduction 183

8.2 DNA Damage Response 184

8.3 Synthetic Lethality 185

8.4 Lead Case Study: PARP Inhibitors 188

8.4.1 Introduction 188

8.4.2 Discovery of PARP Inhibitors 189

8.4.3 Clinical Development of PARP Inhibitors 190

8.4.4 Future for PARP Inhibitors 192

8.5 Additional Case Studies 194

8.5.1 MLH1/MSH2 194

8.5.2 p53-ATM 197

8.5.3 Chk1-DNA Repair 197

8.5.4 DNA-PK – mTOR 197

8.5.5 DNA Ligases 198

8.5.6 WEE1 198

8.5.7 APE1 198

8.5.8 MGMT 199

8.5.9 RAD51 199

8.6 Screening for Synthetic Lethality 199

8.6.1 RAS 202

8.6.2 VHL 202

8.6.3 MRN 203

8.7 Contextual Synthetic Lethality Screening 203

8.8 Cancer Stem Cells 204

8.9 Conclusions and Future Directions 204

References 205

9 Amyloid Chemical Probes and Theranostics: Steps Toward Personalized Medicine in Neurodegenerative Diseases 211
Maria Laura Bolognesi

9.1 Introduction 211

9.2 Amyloid Plaques as the Biomarker in AD 212

9.3 Detecting Amyloid Plaques in Patients: from Alois Alzheimer to Amyvid and Beyond 214

9.4 Same Causes, Same Imaging Agents? 218

9.5 Theranostics in AD 219

9.6 Conclusions and Perspectives 220

References 222

10 From Human Genetics to Drug Candidates: An Industrial Perspective on LRRK2 Inhibition as a Treatment for Parkinson’s Disease 227
Haitao Zhu, Huifen Chen, William Cho, Anthony A. Estrada, and Zachary K. Sweeney

10.1 Introduction 227

10.2 Biochemical Studies of LRRK2 Function 229

10.3 Cellular Studies of LRRK2 Function 230

10.4 Animal Models of LRRK2 Function 233

10.5 Clinical Studies of LRRK2-Associated PD and Future Prospects 234

10.6 Small-Molecule Inhibitors of LRRK2 236

10.7 Structural Models of the LRRK2 Kinase Domain 237

10.8 Strategies Used to Identify LRRK2 Kinase Inhibitors (Overview) 238

10.9 Conclusions 246

References 247

11 Therapeutic Potential of Kinases in Asthma 255
Dramane Lainé, Matthew Lucas, Francisco Lopez-Tapia, and Stephen Lynch

11.1 Introduction 255

11.2 Mitogen-Activated Protein Kinases 256

11.2.1 p38 257

11.2.2 JNK 259

11.2.3 ERK 260

11.3 Nonreceptor Protein Tyrosine Kinases 261

11.3.1 Syk 261

11.3.2 Lck 263

11.3.3 JAK 264

11.3.4 ITK 265

11.3.5 Btk 266

11.4 Receptor Tyrosine Kinases 266

11.4.1 EGFR 267

11.4.2 c-Kit 268

11.4.3 PDGFR 269

11.4.4 VEGFR 270

11.5 Phosphatidylinositol-3 Kinases 270

11.6 AGC Kinases 272

11.6.1 PKC 272

11.6.2 ROCK 273

11.7 IkB Kinase 275

11.8 Other Kinases 276

11.8.1 SphK 276

11.8.2 GSK-3b 277

11.9 Conclusions: Future Directions 278

References 279

12 Developing Targeted PET Tracers in the Era of Personalized Medicine 289
Sandra M. Sanabria Bohorquez, Nicholas van Bruggen, and Jan Marik

12.1 Imaging and Pharmacodynamics Biomarkers in Drug Development 289

12.2 General Considerations for Development of 11C- and 18F-labeled PET Tracers 292

12.3 Radiolabeling Compounds with 11C 294

12.3.1 Preparation of 11C and Basic Reactive Intermediates 294

12.3.2 11C-Methylations, Formation of 11C__X Bond (X=O, N, S) 295

12.3.3 11C-Methylations, Formation of 11C__C Bond 297

12.3.4 Reactions with 11CO2 299

12.3.5 Reactions with 11CO 301

12.3.6 Reactions with H11 CN 303

12.4 Radiolabeling Compounds with 18F 304

12.4.1 Formation of C__18F Bond, Nucleophilic Substitutions 304

12.4.2 Aliphatic Nucleophilic 18F-Fluorination 306

12.4.3 Aromatic Nucleophilic 18F-Fluorination 309

12.4.4 Electrophilic 18F-Fluorination 313

12.4.5 Formation of 18F-Al, Si, B Bond 314

12.5 PET Imaging in the Clinic, Research, and Drug Development 315

12.5.1 PET in Oncology 315

12.5.2 PET Neuroimaging 317

12.5.3 PET in Cardiology 319

12.6 PET Tracer Kinetic Modeling for Quantification of Tracer Uptake 320

12.7 Concluding Remarks 325

References 325

13 Medicinal Chemistry in the Context of the Human Genome 343
Andreas Brunschweiger and Jonathan Hall

13.1 Introduction 343

13.2 Drugs Targeting Kinases 344

13.3 Drugs Targeting Phosphatases 347

13.4 In silico-Based Lead Discovery in the GPCR Family 348

13.5 Targeting Epigenetic Regulation: Histone Demethylases 350

13.6 Targeting Epigenetic Regulation: Histone Deacetylases 351

13.7 A Family-Wide Approach to Poly(ADP-Ribose) Polymerases 352

13.8 Future Drug Target Superfamilies: Ubiquitination and Deubiquitination 353

13.9 Summary and Outlook 354

References 355

Index 365

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