Medicinal Chemistry Approaches to Personalized Medicine E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Serie: Methods and Principles in Medicinal Chemistry
• Sprache: Englisch

Seitenzahl: 765

Veröffentlichungsjahr: 2013

Beschreibung

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

Leseprobe

Contents

Cover

Methods and Principles in Medicinal Chemistry

Title Page

Copyright

List of Contributors

Foreword

Preface

A Personal Foreword

Acronyms

Chapter 1: Medicinal Chemistry Approaches to Creating Targeted Medicines

1.1 Introduction

1.2 Role of Medicinal Chemistry in Drug Discovery

1.3 Evolution of Molecular Design for Subsets of Patients

1.4 Combinations for Effective Therapies

1.5 Biomarkers in Targeting Patients

1.6 Emerging Field of Epigenetics

1.7 Systems Chemical Biology

1.8 Theranostics and Designing Drug Delivery Systems

1.9 Rapid Progress in Further Personalizing Medicine Expected

References

Chapter 2: Discovery of Predictive Biomarkers for Anticancer Drugs

2.1 Introduction

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

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

2.4 Modeling Drug Resistance to Discover Predictive Biomarkers

2.5 Discovery of Predictive Biomarkers in the Context of Treatment Combinations

2.6 Discovery of Predictive Biomarkers for Antiangiogenic Agents

2.7 Gene Expression Signatures as Predictive Biomarkers

2.8 Current Challenges in Discovering Predictive Biomarkers

2.9 Future Perspective

References

Chapter 3: Crizotinib

3.1 Introduction

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

3.3 Kinase Selectivity of Crizotinib

3.4 Pharmacology of Crizotinib [45,46]

3.5 Human Clinical Efficacies of Crizotinib

3.6 Summary

References

Chapter 4: Discovery and Development of Vemurafenib: First-in-Class Inhibitor of Mutant BRAF for the Treatment of Cancer

4.1 Background

4.2 Discovery and Development of Vemurafenib (PLX4032)

4.3 Pharmacology

4.4 Clinical Efficacy and Safety

4.5 Companion Diagnostic (cobas 4800) Development

4.6 Synthesis

4.7 Summary

References

Chapter 5: Targeting Basal-Cell Carcinoma: Discovery and Development of Vismodegib (GDC -0449), a First-in-Class Inhibitor of the Hedgehog Pathway

5.1 Introduction

5.2 Hedgehog and Basal-Cell Carcinoma

5.3 Cyclopamine as an SMO Antagonist

5.4 Small-Molecule Inhibitors of SMO

5.5 Preclinical Characterization of Vismodegib

5.6 Vismodegib Clinical Experience in Phase I

References

Chapter 6: G-Quadruplexes as Therapeutic Targets in Cancer

6.1 Introduction

6.2 Quadruplex Fundamentals

6.3 Genomic Quadruplexes

6.4 Quadruplexes in Human Telomeres

6.5 Quadruplexes as Anticancer Targets – Evidence from In Vivo Studies

6.6 Native Quadruplex Structures

6.7 Quadruplex–Small-Molecule Structures

6.8 Developing Superior Quadruplex-Binding Ligands

6.9 Conclusions

References

Chapter 7: Identifying Actionable Targets in Cancer Patients

7.1 Introduction and Background

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

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

7.4 Some Experiences of Other Clinical Oncology Molecular Profiling Studies

7.5 Identifying Secondary and Novel Mutations through Molecular Profiling

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

7.7 Concluding Remarks and Future Perspectives

References

Chapter 8: DNA Damage Repair Pathways and Synthetic Lethality

8.1 Introduction

8.2 DNA Damage Response

8.3 Synthetic Lethality

8.4 Lead Case Study: PARP Inhibitors

8.5 Additional Case Studies

8.6 Screening for Synthetic Lethality

8.7 Contextual Synthetic Lethality Screening

8.8 Cancer Stem Cells

8.9 Conclusions and Future Directions

References

Chapter 9: Amyloid Chemical Probes and Theranostics: Steps Toward Personalized Medicine in Neurodegenerative Diseases

9.1 Introduction

9.2 Amyloid Plaques as the Biomarker in AD

9.3 Detecting Amyloid Plaques in Patients: from A lois A lzheimer to A myvid and Beyond

9.4 Same Causes, Same Imaging Agents?

9.5 Theranostics in AD

9.6 Conclusions and Perspectives

References

Chapter 10: From Human Genetics to Drug Candidates: An Industrial Perspective on LRRK2 Inhibition as a Treatment for Parkinson's Disease

10.1 Introduction

10.2 Biochemical Studies of LRRK 2 Function

10.3 Cellular Studies of LRRK 2 Function

10.4 Animal Models of LRRK 2 Function

10.5 Clinical Studies of LRRK 2-Associated PD and Future Prospects

10.6 Small-Molecule Inhibitors of LRRK 2

10.7 Structural Models of the LRRK 2 Kinase Domain

10.8 Strategies Used to Identify LRRK 2 Kinase Inhibitors (Overview)

10.9 Conclusions

References

Chapter 11: Therapeutic Potential of Kinases in Asthma

11.1 Introduction

11.2 Mitogen-Activated Protein Kinases

11.3 Nonreceptor Protein Tyrosine Kinases

11.4 Receptor Tyrosine Kinases

11.5 Phosphatidylinositol-3 Kinases

11.6 AGC Kinases

11.7 IκB Kinase

11.8 Other Kinases

11.9 Conclusions: Future Directions

References

Chapter 12: Developing Targeted PET Tracers in the Era of Personalized Medicine

12.1 Imaging and Pharmacodynamics Biomarkers in Drug Development

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

12.3 Radiolabeling Compounds with 11C

12.4 Radiolabeling Compounds with 18F

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

12.6 PET Tracer Kinetic Modeling for Quantification of Tracer Uptake

12.7 Concluding Remarks

References

Chapter 13: Medicinal Chemistry in the Context of the Human Genome

13.1 Introduction

13.2 Drugs Targeting Kinases

13.3 Drugs Targeting Phosphatases

13.4 In silico -Based Lead Discovery in the GPCR Family

13.5 Targeting Epigenetic Regulation: Histone Demethylases

13.6 Targeting Epigenetic Regulation: Histone Deacetylases

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

13.8 Future Drug Target Superfamilies: Ubiquitination and Deubiquitination

13.9 Summary and Outlook

References

Index

Methods and Principles in Medicinal Chemistry

Edited by R. Mannhold, H. Kubinyi, G. Folkers

Editorial Board

H. Buschmann, H. Timmerman, H. van de Waterbeemd, T. Wieland

Previous Volumes of this Series:

Brown, Nathan (Ed.)

Scaffold Hopping in Medicinal Chemistry

2014

ISBN: 978-3-527-33364-6

Vol. 58

Hoffmann, Rémy D. / Gohier, Arnaud / Pospisil, Pavel (Eds.)

Data Mining in Drug Discovery

2014

ISBN: 978-3-527-32984-7

Vol. 57

Dömling, Alexander (Ed.)

Protein-Protein Interactions in Drug Discovery

2013

ISBN: 978-3-527-33107-9

Vol. 56

Kalgutkar, Amit S. / Dalvie, Deepak / Obach, R. Scott / Smith, Dennis A.

Reactive Drug Metabolites

2012

ISBN: 978-3-527-33085-0

Vol. 55

Brown, Nathan (Ed.)

Bioisosteres in Medicinal Chemistry

2012

ISBN: 978-3-527-33015-7

Vol. 54

Gohlke, Holger (Ed.)

Protein-Ligand Interactions

2012

ISBN: 978-3-527-32966-3

Vol. 53

Kappe, C. Oliver / Stadler, Alexander / Dallinger, Doris

Microwaves in Organic and Medicinal Chemistry

Second, Completely Revised and Enlarged Edition

2012

ISBN: 978-3-527-33185-7

Vol. 52

Smith, Dennis A. / Allerton, Charlotte / Kalgutkar, Amit S. / van de Waterbeemd, Han / Walker, Don K.

Pharmacokinetics and Metabolism in Drug Design

Third, Revised and Updated Edition

2012

ISBN: 978-3-527-32954-0

Vol. 51

De Clercq, Erik (Ed.)

Antiviral Drug Strategies

2011

ISBN: 978-3-527-32696-9

Vol. 50

Klebl, Bert / Müller, Gerhard / Hamacher, Michael (Eds.)

Protein Kinases as Drug Targets

2011

ISBN: 978-3-527-31790-5

Vol. 49

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List of Contributors

Rima Al-awar

Ontario Institute for Cancer Research

MaRS Centre

101 College Street

Toronto, ON M5G 0A3

Canada

Lisa D. Belmont

Genentech Inc.

Oncology Diagnostics

MS 411A, 1 DNA Way

South San Francisco, CA 94080

USA

Gideon Bollag

Plexxikon Inc.

Research

91 Bolivar Drive

Berkeley, CA 94710

USA

Maria Laura Bolognesi

Dipartimento di Farmacia e

Biotecnologie

Via Belmeloro, 6

40126 Bologna, Italy

Italy

Richard Bourgon

Genentech Inc.

Oncology Bioinformatics

MS 411A, 1 DNA Way

South San Francisco, CA 94080

USA

Andrew M.K. Brown

Ontario Institute for Cancer Research

MaRS Centre

101 College Street

Toronto, ON M5G 0A3

Canada

Andreas Brunschweiger

Technische Universität Dortmund

Fakultät Chemie

Chemische Biologie

Otto-Hahn-Strasse 6

44227 Dortmund

Germany

Huifen Chen

Genentech Inc.

Discovery Chemistry

1 DNA Way

South San Francisco, CA 94080

USA

William Cho

Genentech Inc.

Early Clinical Development

1 DNA Way

South San Francisco, CA 94080

USA

Jean Cui

Pfizer Worldwide Research and Development

La Jolla Laboratories

Cancer Chemistry

10770 Science Center Drive

San Diego, CA 92121

USA

Janet Dancey

Ontario Institute for Cancer Research

MaRS Centre

101 College Street

Toronto, ON M5G 0A3

Canada

Martin P. Edwards

Pfizer Worldwide Research and Development

La Jolla Laboratories

Cancer Chemistry

10770 Science Center Drive

San Diego, CA 92121

USA

Anthony A. Estrada

Genentech Inc.

Discovery Chemistry

1 DNA Way

South San Francisco, CA 94080

USA

Marie Evangelista

Genentech Inc.

Oncology Diagnostics

MS 411A, 1 DNA Way

South San Francisco, CA 94080

USA

Gaston Habets

Plexxikon Inc.

Assay & Screening

91 Bolivar Drive

Berkeley, CA 94710

USA

Jonathan Hall

ETH Zürich

Institute of Pharmaceutical Sciences

Wolfgang-Pauli-Str. 10

8093 Zürich

Switzerland

Xiaodong Huang

Genentech Inc.

Oncology Diagnostics

MS 411A, 1 DNA Way

South San Francisco, CA 94080

USA

Prabha Ibrahim

Plexxikon Inc.

Non-Clinical Development

91 Bolivar Drive

Berkeley, CA 94710

USA

Robert S. Kania

Pfizer Worldwide Research and Development

La Jolla Laboratories

Cancer Chemistry

10770 Science Center Drive

San Diego, CA 92121

USA

Karen Lackey

JanAush LLCCharleston, SC 29425USA

Dramane Lainé

Hoffmann-La Roche, Inc.

340 Kingsland Street

Nutley, NJ 07110

USA

Francisco Lopez-Tapia

Hoffmann-La Roche, Inc.

340 Kingsland Street

Nutley, NJ 07110

USA

Matthew Lucas

Hoffmann-La Roche, Inc.

340 Kingsland Street

Nutley, NJ 07110

USA

Stephen Lynch

Hoffmann-La Roche, Inc.

340 Kingsland Street

Nutley, NJ 07110

USA

Jan Marik

Genentech, Inc.

Biomedical Imaging

1 DNA Way

South san Francisco, CA 94080

USA

James C. Marsters Jr.

Genentech Inc.

PM & O

1 DNA Way, MS 16a

South San Francisco, CA 94080

USA

John McPherson

Ontario Institute for Cancer Research

MaRS Centre

101 College Street

Toronto, ON M5G 0A3

Canada

Stephen Neidle

University College London

School of Pharmacy

29-39 Brunswick Square

London WC1N 1AX

UK

Richard M. Neve

Genentech Inc.

Discovery Oncology

MS 411A, 1 DNA Way

South San Francisco, CA 94080

USA

Bruce D. Roth

Genentech Inc.

Discovery Chemistry

1 DNA Way

South San Francisco, CA 94080

USA

Sandra M. Sanabria Bohorquez

Genentech, Inc.

Clinical Imaging Group

1 DNA Way

South san Francisco, CA 94080

USA

Maike Schmidt

Genentech Inc.

Oncology Diagnostics

MS 411A, 1 DNA Way

South San Francisco, CA 94080

USA

Jeffrey Settleman

Genentech Inc.

Discovery Oncology

MS 411A, 1 DNA Way

South San Francisco, CA 94080

USA

Zachary K. Sweeney

Novartis

Global Discovery Chemistry

4560 Horton St.

Emeryville, CA 94608-2916

USA

James Tsai

Plexxikon Inc.

Pharmacology

91 Bolivar Drive

Berkeley, CA 94710

USA

David Uehling

Ontario Institute for Cancer Research

MaRS Centre

101 College Street

Toronto, ON M5G 0A3

Canada

Nicholas van Bruggen

Genentech, Inc.

Biomedical Imaging

1 DNA Way

South san Francisco, CA 94080

USA

Simon Ward

Translational Drug Discovery Group, University of Sussex, Brighton, BN1 9QJ, UK

Harvey Wong

Genentech Inc.

Drug Metabolism and Pharmacokinetics

1 DNA Way, MS 16a

South San Francisco, CA 94080

USA

Robert L. Yauch

Genentech Inc.

Oncology Diagnostics

MS 411A, 1 DNA Way

South San Francisco, CA 94080

USA

Chao Zhang

Plexxikon Inc.

Informatics & Structural Chemisty

91 Bolivar Drive

Berkeley, CA 94710

USA

Jiazhong Zhang

Plexxikon Inc.

Chemistry

91 Bolivar Drive

Berkeley, CA 94710

USA

Haitao Zhu

Genentech Inc.

Neuroscience

1 DNA Way

South San Francisco, CA 94080

USA

Foreword

Over the past decade, major advances have been made in elucidating the pathophysiological processes involved in many human diseases, including solid and hematological malignancies, hepatitis C, asthma, Alzheimer's disease, Parkinson's disease, age-related macular edema, and even diabetes. We know more about the biology of human disease than ever before, yet most diseases are still classified by their clinical presentation, associated physical exam, imaging data, and laboratory abnormalities. Only a few diseases are defined by the molecular pathways that cause the disease.

Using a “clinically” oriented approach to medicine results in profound heterogeneity in the molecular underpinnings of a given disease. Compounding this problem is that this heterogeneity has traditionally not been taken into account when studies were designed to evaluate a new molecular entity in a given disease. As an example, in 2005, Peagram et al. performed a Medline literature search using the keyword “epidermal growth factor receptor” (EGFR) and found 13 569 citations. Despite this intense level of scientific investigation into the EGFR, it was not until 2004 that important mutations in the kinase domain of the EGFR that identifies patients who are particularly sensitive to the effects of small-molecule tyrosine kinase inhibitors such as gefitinib or erlotinib were first reported. This lack of insight contributed to the numerous failed studies in the frontline non-small cell lung cancer setting when these inhibitors were given to an all-comers population. The authors of this paper also performed simulations to model the impact of including patients in a clinical trial whose disease is not sensitive to a given drug's treatment effect. They simulated administering a highly effective treatment to women with newly diagnosed metastatic breast cancer and found that when a diagnostic was used to select those patients most likely to benefit, the clinical trial was robustly positive. When the percentage of patients who would not benefit was increased, the treatment effect waned. Importantly, if only 25% of patients benefited (as is roughly the case with Herceptin for women with Her2 overexpressing breast cancer), studying an unselected population in a clinical trial (i.e., where 75% are unlikely to benefit) would result in survival curves that are essentially overlapping. In other words, without appreciating this heterogeneity in disease biology, a clinical trial evaluating a potentially important new therapy would be negative without a diagnostic to identify those most likely to benefit.

The pharmaceutical industry is under intense pressure to improve R&D productivity. This is in large part driven by increasing costs associated with conducting clinical trials compounded by very low success rates once a drug enters clinical testing. One cannot help but wonder how many of the over 90% of drugs that fail during clinical development would have succeeded had more attention been given to identifying the population most likely to benefit.

Fortunately, over the past decade and in particular the last several years, there has been a marked shift in the discovery and development process to incorporate these concepts. Advances in cellular and molecular biology, human genetics, translational medicine (including biomarkers and diagnostics), and innovative clinical trials designs have enabled us to enter the era of so-called personalized health care (PHC). This is leading to some of the most promising new therapies ever developed in the history of medicine. In oncology alone, this new era of medicine has resulted in numerous new drugs for patients. As of 2013, the NCI website has identified over 40 “targeted therapies,” although not all of these new medicines would meet the strict definition described above.

For some of these new therapies, we have observed treatment effects of almost unparalleled nature, a shorter time in clinical development, and although it is still in early days, it appears that the success rates are also likely to exceed industry averages.

It should also be pointed out that while the advances in personalized health care have been extremely impressive in oncology drug development, a similar targeted strategy is being embraced in the fields of immunology, neuroscience, and other areas of medicine. It should also be highlighted that while for most areas of medicine PHC is only recently being embraced, the field of infectious disease has adopted this concept for decades. The idea that all cases of “pneumonia” are not the same is today taken for granted. The technology for understanding the pathophysiology of this disease required much less sophisticated tools (i.e., the microscope and Petri dishes). This leads to subclassification of pneumonia by the causal agent with different treatments being prescribed based on the presumed organism responsible for the disease.

With the sequencing of the human genome over a decade ago and an increasingly sophisticated understanding of the pathophysiology of human disease-based metabolomics, proteomics, and other tools, we have clearly ushered in a new era in drug discovery and development. The end result is likely to have a very meaningful and lasting impact on academia, biotechnology and pharmaceutical companies, payers, health care providers, and most importantly patients.

Surprisingly, despite the importance of personalized health care in so many recent advances in drug therapy, there have been few attempts to collect the success stories across industry and academia that have advanced research toward new, targeted therapies. This book, therefore, fills this gap in the literature and thus should be a useful resource for pharmaceutical and biopharmaceutical researchers for years to come.

Executive Vice President, Global Product Development Chief Medical Officer Genentech Inc., 1 DNA Way South San Francisco, CA 94080

Hal Barron, MD

F. Hoffmann-La Roche Ltd.

Preface

The notion of personalized medicine, in both the laity and the scientific community, is very often associated with screening, genetic profiling, and risk stratification. While it is unquestioned that genomics is the starting point of future “targeted medicine,” personal genomics and individual genetic testing for risk stratification are still under public debate, because of their ethical and legal implications. Therefore, an account of how all this collected genetic information translates into therapeutic practice and how it may do so in near future is of highest importance not only for the public dialogue but also for the experts in drug design and development.

This book provides such an account. Edited by Karen Lackey and Bruce D. Roth, both fundamentally involved in the topic, the book convenes experts from the medicinal chemistry field in the private sector and the academia to provide their perspectives on personalized medicine. Naturally, the scope is broad. The book consisting of 13 chapters covers a more general content on feasibility of medchem approaches, contrasted by those that describe case studies of successful implementations and also others that open up new field to explore. In addition to cancer – the therapeutic area one would expect to have been mainly covered, neurodegenerative diseases such as Alzheimer's and Parkinson's diseases as well as asthma have also been studied in this book. Methodological approaches and targets besides “chemistry” range from molecular profiling, G-quadruplexes, amyloid probes, and PET to histones, plaques in the brain, kinases, ubiquination as a future target superfamily, and DNA repair pathways.

Of course, any book on this broad topic cannot be comprehensive or even encyclopedic. The translational process of personalized medicine is in full swing and many economical questions either for the private sector or for patients and social security systems remain to be solved.

The book parallels success stories – that have been long overdue to be reported – with recent and future developments in the field.

In this respect, it is not only at cutting edge in the field but also fulfills in an excellent way the requirement of this series to serve as a handbook for bench chemists, developers, and the academic realm of research and teaching. Especially teachers may feel encouraged to use the eminent expert information collected, to challenge their students with this extension in medicinal chemistry to a medicine of the future.

The series editors are indebted to the authors and the editors who made it possible to cover this very essential issue.

We are also very much indebted to Heike Nöthe and Frank Weinreich, both at Wiley-VCH. Their support and ongoing engagement not only for this book but also for the whole series Methods and Principles in Medicinal Chemistry greatly contribute to the success of this excellent collection related to drug research.

Düsseldorf

Weisenheim am Sand

Zürich

October 2013

Raimund Mannhold

Hugo Kubinyi

Gerd Folkers

A Personal Foreword

Personalized medicine and personalized healthcare have become virtual buzzwords used by the lay press and the pharmaceutical and biopharmaceutical industries in describing their current approaches to drug discovery and development aimed at providing patients with individualized therapies. Many established and emerging companies have even suggested that this is the foundation for their business strategy. Fundamentally, creating personalized medicine requires the integration of multiple disciplines, including medicinal chemistry, genetics, diagnostics, biochemistry, cellular biology, pharmacology, formulations, and clinical sciences, in order to ensure that patients have access to and are prescribed medicines with the highest likelihood of effectively treating their specific disease – and that patients unlikely to respond are not given drugs from which they will likely not receive benefit. The ultimate goal of the medical field is to have drugs that treat the underlying causes of the disease pathology. This approach has many benefits: to the companies, lower costs and higher success rates; for the patients, more effective therapies with better risk/benefit ratios. In fact, over the last several decades, many drugs, both small molecules and biologics, have been discovered and developed that would fall under this umbrella, especially in the treatment of cancer, where the emphasis on personalized medicine has led to greatly improved success rates in bringing new medicines to the market. Despite this emphasis on personalized medicine in the last decade, there has been no comprehensive treatment of this subject focusing specifically on the role of the medicinal chemist in this process, despite the fact that virtually all small-molecule drugs originate in the mind of the medicinal chemist.

In this book, we have attempted to bring together the collective experience of the pharmaceutical industry and academia, across multiple therapeutic areas and disciplines, in an attempt to capture the full spectrum of activities in implementing personalized medicine. Thus, we have chapters providing case studies of several recently approved “targeted therapies” in oncology where personalized medicine is most mature, but there are also chapters that cover developments in other therapeutic areas, development of diagnostics, imaging, and several on different aspects of new target discovery. Our hope is that this book will not only be a useful review of past practices in the discovery and development of personalized medicine but will also lay the foundation for future advances in bringing life-changing, transformative medicines to patients. Ultimately, the goal of all of those who have committed their lives and energies to medicinal sciences is to bring benefit to the patients who are desperately waiting for the drugs that arise from the incredible scientific discoveries emanating from the work of these dedicated researchers.

Finally, we would like to thank all of the more than 40 authors and contributors to this book as well as the support and encouragement of Dr Heike Nöthe and Dr Frank Weinreich of Wiley-VCH. We are also greatly indebted to Ms Christine Cumberton for the finalization and compilation of chapters for submission to the publisher.

Nutley, NJ

South San Francisco, CA

June 2013

Karen Lackey

Bruce D. Roth

Acronyms

AChE(I)acetylcholine esterase (inhibitor)ADAlzheimer's diseaseADCantibody drug conjugatesADMEabsorption, distribution, metabolism, and excretionAEadverse eventsAGCprotein kinase A, G, and C familiesAHRairway hyperresponsivenessALCLanaplastic large-cell lymphomaALKanaplastic lymphoma kinaseAP-1activating protein 1APCadenomatous polyposis coli geneAPPamyloid precursor proteinATPadenosine triphosphateAUCarea under the curveBBBblood–brain barrierBCCbasal-cell carcinomaBCRPbreast cancer resistance proteinBERbase excision repairBIDbis in die (Latin) meaning twice a dayBPbinding proteinCADcoronary artery diseaseCBDcorticobasal degenerationCETPcholesteryl ester transfer proteinCHMPCommittee for Medicinal Products for Human UseCIAcollagen-induced arthritisCIconfidence intervalCLRclearance rateCMLchronic myelogenous leukemiaCNScentral nervous systemCNVcopy number variationsCOPDchronic obstructive pulmonary disorderCRcomplete responseCRCcolorectal cancerCSFcerebral spinal fluidCTCcirculating tumor cellsCUPcarcinoma of unknown primaryCDKcyclin-dependent kinaseCOMTcatechol-O-methyl transferaseDAGdiacylglycerolDATdopamine transporterDCRdisease control rateDDRDNA damage responseDECPdiethyl cyanophosphonateDLBdementia with Lewy bodiesDMFdimethylformamideDMSOdimethylsulfoxideDNAdeoxyribonucleic acidDRdirect repairDUPA(dicarboxypropyl)ureidopentanedioic acidERestrogen receptorErbB2erythroblastic leukemia oncogene homolog 2, also known as HER2/NeuERKextracellular regulating kinaseFAM6-carboxyfluoresceinFBDDfragment-based drug discoveryFBLDfragment-based ligand discoveryFDAFood and Drug AdministrationFDGfluoro-deoxy-d-glucoseFFPETformalin fixed paraffin embedded tissueFISHfluorescence in situ hybridizationFRETfluorescence resonance energy transferFTDfrontotemporal dementiaGEMMgenetically engineered mouse modelGIMgenetic interaction mappingGISTgastrointestinal stromal tumorsGLUTglucose transport proteinsGSKglycogen synthase kinaseGTPaseguanine triphosphataseGWASgenome-wide association studiesHDAChistone deacetylasesHDMhistone demethylasesHER2human epidermal growth factor receptor 2hERGhuman ether-a-go-go related geneHGF(R)hepatocyte growth factor (receptor)HhhedgehogHIFhypoxia inducible factorHRhomologous recombinationsHSPheat shock proteinHTShigh-throughput screeningIC50concentration at 50% inhibitionICGCInternational Cancer Genome ConsortiumICSinhaled corticosteroidsIGF(R)insulin growth factor (receptor)IHCimmunohistochemistryIL-1interleukin-1IMTinflammatory myofibroblastic tumorsINDELinsertions or deletions of a short coding regionITKinterleukin-2-inducible T-cell kinaseIVintravenousLABAlong acting beta-2 agonistsLEligand efficiencyLipElipophilic efficiencyLNlymph nodeMAOmonoamine oxidaseMAPKmitogen-activated protein kinaseMBCmetastatic breast cancerMBPmicroprecipitated bulk powderMCImild cognitive impairmentMCTmethylcellulose TweenMGMTO-(6)-methylguanine-DNA methyltransferaseMKmidkineMLCmyosin light chainMLKmixed lineage kinaseMMRmismatch repairMMSEminimental state examinationMOMmethoxymethylMPmolecular profilingMPImyocardial perfusion imagingMRImagnetic resonance imagingMRTmean residence timeMTDmaximum tolerated doseMTEBmetabotropic glutamate receptor typemTORmammalian target of rapamycinNAnot applicableNCINational Cancer InstituteNERnucleotide excision repairNETnorepinephrine transporterNFTneurofibrillary tanglesNGSnext-generation sequencersNHEJnonhomologous end joiningNHLnon-Hodgkin lymphomaNIHNational Institute of HealthNKnatural killerNMEnew molecular entityNMRnuclear magnetic resonanceNOAELno adverse effect levelNPMnucleophosminNRTKnonreceptor tyrosine kinaseNSCLCnon-small cell lung cancerOICROntario Institute for Cancer ResearchORRoverall response rateOSoverall survivalPARPpoly-ADP-ribose polymerasePASperipheral anionic sitePBCApoly(butyl-2-cyanoacrylate)PCRpolymerase chain reactionPDpharmacodynamic or progressive disease or Parkinson's diseasePDACpancreatic cancer-ductal adenocarcinomaPDBProtein Data 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receptorSNPsingle-nucleotide polymorphismSPECTsingle-photon emission computed tomographySphKsphingosine kinaseSPRsurface plasmon resonanceSTKserine threonine kinaseSykspleen tyrosine kinaseTACtime activity curveTAMRA6-carboxytetramethylrhodamineTBAFtetrabutylammonium fluorideTBItraumatic brain injuryTERRAtelomeric repeat-containing RNATETten-eleven translocationThTthioflavin-TTKItyrosine kinase inhibitorTKLtyrosine kinase-likeTNFtumor necrosis factorUSUnited StatesUVultravioletVEGF(R)vascular endothelial growth factor (receptor)VMATvesicular monoamine transporterW3CWorld Wide Web ConsortiumWESwhole-exome sequencing

1

Medicinal Chemistry Approaches to Creating Targeted Medicines

Bruce D. Roth and Karen Lackey

1.1 Introduction

Personalized medicines are therapies that maximize the biological effectiveness of treatment by targeting the molecular drivers of the disease through a deep understanding of disease biology, identifying and treating the patients most likely to respond based on personal genomics, metabolomics, proteomics, and perhaps epigenomics. This ability to very selectively target appropriate patient populations has become the foundation of much of drug discovery in the past decade due to the remarkable advances in molecular biology and diagnostics that have enabled the understanding of many diseases at the genomic level. Personalized medicine has become even more important, as healthcare costs continue to soar, such that creating the ideal situation where patients would only receive a potent, safe, and efficacious drug that treats their specific disease at a dose that is titrated for their metabolism has become an ethical, a societal, and an economic imperative. The state of personalized medicine today finds different therapeutic areas at very different stages of development. For oncology most of the personalized medicine approaches reflect attempts to design drugs that very selectively target the drivers of a patient's specific cancer. In diseases of neuroscience, current personalized approaches attempt to treat these complex diseases through polypharmacy. For inflammatory diseases, personalized medicine requires strategies for subsetting patients to ensure that the medicine is treating the underlying causes of the disease. In all of these therapeutic areas, the role of medicinal chemistry is to create drugs with very specific properties and biological activities to achieve the objectives of personalization of medical care. The techniques and strategies needed by medicinal chemists ranging from identifying active compounds to optimizing chemical series for the intended patient population, delivery route, and combination therapy required to enable personalized medicine will be discussed in this book. This book will cover the meaning of personalized medicine, its importance, how it is implemented, and how medicinal chemistry has evolved to facilitate it. Since drug discovery research to achieve personalized health care is being conducted in academia, biotechnology companies, pharmaceutical companies, and research institutes, we have tried to ensure representation from all of these institutions as chapter authors. Because therapeutic areas are in such different stages of achieving personalized medicine, we have dedicated sections of the book to cover the state of the art in oncology, neurosciences, and inflammation to demonstrate the diversity of approaches. Gleevec will be showcased in this introductory chapter as the groundbreaking example of personalized medicine, highlighting the key issues involved, including identification of the intended molecular target and target patient population, expanding the patient population by understanding the drug profile, and the need for alternatively designed drugs to combat resistance and nonresponsive patients. More recent advances in combination therapy and drug delivery will be discussed to show how medicinal chemistry can impact the effectiveness of individualized medicine. Drug repurposing of clinical candidates and marketed medicines can utilize the medicinal chemistry approaches to rapidly achieve personalized medicine goals and will also be covered. We have also included a chapter focused on diagnostics in oncology, an essential aspect of patient identification, highlighting the advanced state of science in this therapeutic area, as well as chapters on approaches to patient stratification in other therapeutic areas and a chapter on imaging as a new diagnostic frontier. The book will conclude with a future perspective on how medicinal chemistry will continue to be the driving force behind translating human genomic information into personalized medicines. Although targeted biologics are an essential part of the armamentarium of drug treatment and have been foundational in the development of personalized medicine, they are beyond the scope of this book and will only be mentioned briefly in this introduction. We will, however, in this introduction touch on the impact of biologics, most notably Herceptin, on the development of personalized medicines, as well as highlighting some of the topics not specifically covered by other authors, such as drug targeting through antibody–drug conjugates and nanoparticles.